CLONAL HEMATOPOIESIS: ROLE IN HEMATOLOGIC NON-HEMATOLOGIC MALIGNANCIES CLONAL HEMATOPOIESIS AND MALIGNANCIES
Main Article Content
Keywords
Abstract
Hematopoietic stem cells (HSCs) ensure the coordinated and balanced production of all hematopoietic cell types throughout life. Aging is associated with a gradual decline of the self-renewal and regenerative potential of HSCs and with the development of clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP) is a term defining the clonal expansion of genetically variant hematopoietic cells bearing one or more gene mutations and/or structural variants (such as copy number alterations). CHIP increases exponentially with age and is associated with cancers, including hematologic neoplasia, cardiovascular and other diseases. The presence of CHIP consistently increases the risk of hematologic malignancy, particularly in individuals who have CHIP in association with peripheral blood cytopenia.
Key words: hematopoiesis, hematopoietic stem cells, clonal hematopoiesis, gene mutations, next generation sequencing.
Downloads
Abstract 871
PDF Downloads 613
HTML Downloads 222
References
2) Tavian M, Robin C, Coulombel L, Péault B. The human embryo, but not its yolk sac, generates lympho-myeloid stem cells: mapping multipotent hematopoietic cell fate in intraembryonic mesoderm. Immunity 2001; 15(3): 487-495.
3) Perdiguero EG, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR. Tissue-resident macrophages originate from yolk-sac-derived erythron-myeloid progenitors. Nature 2015; 518(7540): 547-551.
4) Bian Z, Gong Y, Huang T, Lee C, Bian L, Bai Z, Shi H, Zeng Y, Liu C, He J, Zhou J, Li X, Li Z, Ni Y, Ma C, Cui L, Zhang R, Chan J, Ng LG, Lan Y, Ginhoux F, Liu B. Deciphering human macrophage development at single-cell resolution. Nature 2020; 582(7813): 571-576.
5) Dick SA, Wong A, Hamidzada H, Nejat S, Nechanitzky R, Vohra S, Mueller B, Zaman R, et al. Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles. Sci Immunol 2022; 7(67): eabf7777.
6) Atkins MH, Scarfò R, McGrath KE, Yang D, Palis J, Ditadi A, Keller GM. Modeling human yolk sac hematopoiesis with multipotent stem cells. J Exp Med 2022; 219(3): e20211924.
7) Zhao S, Feng S, Tian Y, Wen Z. Hemogenic and aortic endothelium arise from a common hemogenic angioblast precursor and are specified by the ETV2 dosage. Proc Natl Acad Sci USA 2022; 119(13): e2119051119.
8) Baron CS, Kester L, Klaus A, Boisset JC, Thambyrajah R, Yvernogeau L, Kouskoff V, Lacaud G, van Oudenaarden A, Robin C. Single-cell transcriptomics reveal the dynamic of haematopoietic stem cell production cell production in the aorta. Nature Commun 2018; 9: 2517.
9) Zhu Q, Gao P, Tober J, Bennett L, Chen C, Uzun Y, Li Y, Howell ED, Mumau M, Yu W, He B, Speck NA, Tan K. Developmental trajectory of prehematopoietic stem cell formation from endothelium. Blood 2020; 136(7): 845-856.
10) Hou S, Li Z, Zheng X, Gao Y, Dong J, Ni Y, Wang X, LI Y, Ding X, Chang Z, Li S, Hu Y, Fan X, Hou Y, Wen L, Liu B, Tang F, Lan Y. Embryonic endothelial evolution towards first hematopoietic stem cells revealed by single-cell transcriptomic and functional analyses. Cell Res 2020; 30(3): 376-392.
11) Zeng Y, He J, Bai Z, Li Z, Gong Y, Liu C, Ni Y, Du J, Ma C, Bian L, Lan Y, Liu B. Tracing the firs haematopoietic stem cell generation in human embryo by single-cell RNA sequencing. Cell Res 2019; 29(11): 881-894.
12) Barcena A, Muench MO, Kapidzic M, Fisher SJ. A new role for the human placenta as a hematopoietic site throughout gestation. Reprod Sci 2009; 16(2): 178-187.
13) Van Handel B, Prashad SL, Hassanzadeh-Kiabi N, Huang A, Magnusson M, Atanassova B, Chen A, Hamalainen EI, Mikkola H. The first trimester human placenta is a site for terminal maturation of primitive erythroid cells. Blood 2010; 116(17): 3321-3330.
14) Robin C, Bollerot K, Mendes S, Haak E, Crisa M, Cerisoli F, Lauw I, Kaimakis P, Jorna R, Vermeulen M, Kayser M, van der Linden R, Imarinad P, Verstegen M, Nawaz-Yousaf H, Papazian N, Steegers E, Cupedo T, Dzierzak E. Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell 5(19): 385-395.
15) Muench MO, Kapidzic M, Gormley M, Gutierrez AG, Ponder KL, Fomin ME, Beyer AI, Stolp H, Qi Z, Fisher SJ, Barcena A. The human chorion contains definitive hematopoietic stem cells from the fifteenth week of gestation. Development 2017; 144(8): 1399-1411.
16) Calvanese V, Capellera-Garcia S, Ma F, Fares I, Liebscher S, Ng E, Ekstrand S, Aguadé-Grogorio J, Vavilina A, Lefaudeux D, Nadel B, Li JY, Wang Y, Lee KL, Ardehali R, Iruela-Arispe ML, Pellegrini M, Stanley EG, Elefanty AG, Schenke-Layland K, Mikkola H. Mapping human haematopoietic stem cells from haemogenic endothelium to birth. Nature 2022; 604(7106): 534-540.
17) Holyoake TL, Nicolini FE, Eaves CJ. Functional differences between transplantable human hematopoietic stem cells from fetal liver, cord blood, and adult marrow. Exp Hematol 1999; 29: 927-936.
18) Walter D, Lier A, Geiselhart A, Thalheimer FB, Huntscha S, Sobotta MC, Moehrle B, Brocks D, Bayindir I, Kaschutnig P, et al.Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature 2015; 520(7548): 549-552.
19) Rodriguez-Fraticelli AE, Weinreb CS, Wang SW, Migueles RP, Jankovic M, Usart M, Klein AM, Lowell S, Camargo FD. Single-cell lineage tracing unveils a role for Tcf15 in hematopoiesis. Nature 2020; 583(7817): 585-589.
20) Biswas A, Roy IM, Babu PC, Manesia J, Schouteden S, Vijakakurup V, Anto RJ, Huelsken J, Levy-Hulbert A, Varfaille CM, Khurana S. The periostin/integrin-αV axis regulates the size of hematopoietic stem cell pool in the fetal liver. Stem Cell Rep 2020; 15(2): 340-357.
21) Vanuytsel K, Villacorta-Martin C, Lindstrom-Vautrin J, Wang Z, Garcia-Beltran WF, Vrbanac V, Parsons D, Lam EC, Matte TM, Dowrey TW, et al. Multi-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment. Nat Commun 2022; 13: 1103.
22) Jardine L, Webb S, Goh I, Quiraga Londono M, Reynolds G, Mather M, Olabi B, Stephenson E, Botting RA, Horsfall D, et al. Blood and immune development in human fetal bone marrow and Down syndrome. Nature 2021; 598(7880): 327-331.
23) Li Y, Kong W, Yang W, Patel RM, Casey EB, Okeyo-Owuor T, White JM, Porter SN, Morris SA, Magee JA. Single-cell analysis of neonatal HSC ontogeny reveals gradual and uncoordinated transcriptional reprogramming that begins before birth. Cell Stem Cell 2020; 27(5): 732-747.
24) Catlin SN, Busque L, Gale RE, Guttorp P, Abkowitz JL. The replication of human hematopoietic stem cells in vivo. Blood 2011; 117(17): 4460-4466.
25) Laurenti E, Frelin C, Xie S, Ferrari R, Dunant CF, Zandi S, Neumann A, Plumb I, Doulatov S, Chen J, April C, Iscove N. CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell 2015; 16(3): 302-313.
26) Takayama N, Murison A, Takayanagi SI, Arlidge C, Zhou S, Garcia-Prat L, Chan-Sng-Yue M, Zandi S, Gand OI, Boutzen H, Kaufmann KB, et al. The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization. Cell Stem Cell 2020; 28(3): 488-501.
27) Liang R, Arif T, Kalmykova S, Kasianov A, Lin M, Menon V, Qiu J, Bernitz JM, Moore K, Lin F, Benson DL, Tzavaras N, Mahajan M, Papatsenko D, Ghaffari S. Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency. Cell Stem Cell 2020; 26(3): 359-376.
28) Garcia-Prat L, Kaufmann KB, Schneiter F, Voisin V, Murison A, Chen J, Chan-Sen-Yue M, Gan OI, McLeod JL, Smith SA, Shoong MC, et al. TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate. Cell Stem Cell 2021; 28(10): 1838-1850.
29) Waehstedt M, Ladopoulos V, Hidalgo I, Sanchez Castillo M, Hannah R, Sawan P, Wan H, Dudenhoffer-Pfeifer M, Magnusson M, Norddahl GL, Gottgens B, Bryder D. Critical modulation of hematopoietic lineage fate by hepatic leukemia factor. Cell Rep 2017; 21(8): 2251-2263.
30) Komorowska K, Doyle A, Wahlestedt M, Bubramaniam A, Debnath S, Chen J, Soneji S, Van Hendel B, Mikkola H, Miharada K, Bryder D, Larsson J, Magnusson M. Hepatic leukemic factor maintains quiescence of hematopoietic stem cells and protects the stem cell pool during regeneration. Cell Rep 2017; 21(12): 3514-3523.
31) Yokomizo T, Watanabe N, Umemoto T, Matsuo J, Harai R, Kihara Y, Nakamura E, Tada N, Sato T, Takaku T, Shimono A, Takizawa H, Nakagata N, Mori S, Kurokawa M, Tenen DG, Osato M, Suda T, Komatsu N. Hlf marks the developmental pathway for hematopoietic stem cells but not for erythroid-myeloid progenitors. J Exp Med 2019; 216(7): 1599-1614.
32) Lehnertz B, Chagraoui J, MacRae T, Tomellini E, Corneau S, Mayotte N, Boivin I, Durand A, Gracias D, Sauvageau G. HLF expression defines the human hematopoietic stem cell state. Blood 2021; 138(25): 2642-2654.
33) Calvanese V, Nguyen AT, Bolan TJ, Vavilina A, Su T, Lee LK, Wang Y, Lay FD, Magnusson M, Crooks GM, Kudistan SK, Mikkola H. MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment. Nature 2019; 576(7786): 281-286.
34) Rentas S, Holzapfel N, Belew MS, Pratt G, Voisin V, Wilhelm BJ, Bader GD, Yeo GW, Hope KJ. Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells. Nature 532(7600): 508-511.
35) Belew MS, Bhatia S, Keyvani Chani A, Rentas S, Draper JS, Hope KJ. PLAG1 and USF2 co-regulate expression of Musashi-2 in human hematopoietic stem and progenitor cells. Stem Cell Report 208; 10(4): 1384-1397.
36) Wagner JE, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D, Blazar BR, Tolar J, Le C, Jones J, Cooke MP, Bleul CC. Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 2016; 18(1): 144-155.
37) Cohen S, Roy J, Lachance S, Delisle JS, Marinier A, Busque L, Roy DC, Barabé F, Ahmad I, Bambase N, et al. Hematopoietic stem cells transplantation using single UM171-expanded cord blood: a single-arm, phase 1-2 safety and feasibility study. Lancer Hematol 2020; 7(2): e134-e145.
38) Dumont-Lagace M, Feghaly A, Meunier MC, Finney M, Van’t Hof W, Masson Frenet E, Sauvageau G, Cohen S. UM171 expansion of cord blood improves donor availability and HLA matching for all patients, including minorities. Transplant Cell Ther 2022; S2666-6367(22): in press.
39) Laurenti E, Gottgrns B. From hematopoietic stem cells to complex differentiation landscapes. Nature 2018; 553(7689): 418-426.
40) Kato H, Igarashi K. To be red or white: lineage commitment and maintenance of the hematopoietic system by the “inner myeloid”. Haematologica 2019; 104(10): 1919-1927.
41) Ligett LA, Sankaran VG. Unraveling hematopoiesis through the lens of genomics. Cell 2020; 182(6): 1384-1400.
42) Yamamoto R, Morita Y, Oehara J, Hamanaka S, Onodera M, Rudolph KL, Ema H, Nakauchi H. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell 2013; 154(5): 1112-1126.
43) Yamamoto R, Wilkinson AC, Oehara J, Lan X, Lai CY, Nakauchi Y, Pritchard JK, Nakauchi H. Large-scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell 2018; 22(4): 600-607.
44) Carrelha J, Meng Y, Kettyle LM, Luis TC, Norfo R, Alcolea V, Boukarabila H, Grasso F, Gambardella A, Grover A, Hogstrand K, Lord AM, Sanjuan-Pla A, Woll PS, Nerlov C, Jacobsen SE. Hierarchically related lineage-restricyed fates of multipotent haematopoietic stem cells. Nature 2018; 554(7690): 106-111.
45) Rodriguez-Fraticelli AE, Wolock SL, Weinreb CS, Panero R, Patel SH, Jankovic M, Sun J, Calogero RA, Klein AM, Camargo FD. Clonal analysis of lineage fate in native haematopoiesis. Nature 2018; 553(7687): 212-216.
46) Upadhaya S, Sawai CM, Papalexi E, Rashidfarrokhi A, Jang G, Chattopadhyay P, Satihja R, Raizis B. Kinetics of adult hemopoietic stem cell differentiation in vivo. J Exp Med 2018; 215(11): 2815-2832.
47) Weinreh C, Rodriguez-Fraticelli A, Camargo FD, Klein AM. Lineage tracing on trasncriptional landscapes links state to fate during differentiation. Science 2020; 367(6479): eaaw3381.
48) Pei W, Shang F, Wang X, Fanti AK, Greco A, Busch K, Klapproth K, Zhang Q, Quedenau C, Sauer S, Feyerband TB, Hofer T, Rodewald HR. Resolving fates and single-cell transciptomes of hematopoietic stem cell clones by PolyloxExpress barcoding. Cell Stem Cell 2020; 27(20): 383-395.
49) Velten L, Haas SF, Raffel S, Blasziewicz S, Islam S, Hennig BP, Hirche C, Lutz C, Buss EC, Nowak D, Boch T, Hofmann WK, Ho AD, Huber W, Trumpp A, Essers M, Steinmetz LM. Human hematopoietic stem cell lineage commitment is a continuous process. Nat Cell Biol 2017; 19(4): 271-281.
50) Buenrostro JD, Corces MR, Lareau CA, Wu B, Schep AN, Aryee MJ, Majeti R, Chang HY, Greenleaf WJ. Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation. Cell 2018; 173(6): 1535-1548.
51) Psaila B, Mead AJ. Single-cell approaches reveal novel cellular pathways for megakaryocyte and erythroid differentiation. Blood 2019; 133(13): 1427-1435.
52) Karamitros D, Stoilova B, Aboukhalil Z, Hamey F, Reinisch A, Samitsch M, Quek L, Otto G, Repapi E, Doondeea J, et al. Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. Nat Immunol 2018; 19(1): 85-97.
53) Pellin D, Loperfido M, Baricordi C, Wolock SL, Montepeloso A, Weinberg OK, Biffi A, Klein AM, Biasco L. A A comprehensive single cell transcriptional landscape of human hematopoietic progenitors. Nat Commun 2019; 10(1): 2395.
54) Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 2011; 333(6039): 218-221.
55) Anjos-Afonso F, Buettner F, Mian SA, Rhys H, Perez-Llorat J, Garcia-Albornoz M, Rastogi N, Ariza-McNaughton L, Bonnet D. Single cell analyses identify a highly regenerative and homogeneous human CD34+ hematopoietic stem cell population. Nat Commun 2022; 13(5): 2048.
56) Triana S, Vonfitch D, Jopp-Saile L, Raffel S, Lutz R, Leonce D, Antes M, Hernandez-Malmierca P, Ordonez-Rueda D, Ramasz B, et al. Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states. Nat Immunol 2021; 22(12): 1577-1589.
57) Aksoz M,Gafencu GA, Stoilova B, Buono M, Meng Y, Jakobsen NA, Metzner M, Clark SA, Beveridge R, Thongjuea S, Vyas P, Narlov C. Identification and age-independent increase of platelet biased human hematopoietic stem cells. BioRχIV 2022; in press.
58) Loeffler D, Wehling A, Schneiter F, Zhang Y, Muller-Botticher N, Hoppe PS, Hilsenbeck O, Kakkaliaris KD, Endele M, Schroeder T. Asymmetric lysosome inheritance predicts activation of haematopoietic stem cells. Nature 2019; 573(7774): 426-429.
59) Loeffler D, Schneiter F, Wang W, Wehling A, Kull T, Lengerke C, Manz MG, Schroeder T. Asymmetric organelle inheritance predicts human blood stem cell fate. Blood 2022; 139(13): 2011-2023.
60) Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, Klein A, Hofmann O, Camargo FD. Clonal dynamics of native haematopoiesis. Nature 2014; 14(7522): 322-327.
61) Bush K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner SM, Reth M, Hofer T, Rodewald HR. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 2015; 518(7540): 542-546.
62) Sawai C, Babovic S, Upadhaya S, Knapp D, Lavin Y, Lau C, Goloborodko A, Feng J, Fujisaki J, Ding L, Mirny LA, Merad M, Eaves CJ, Reizis B. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity 2016; 45(16): 597-609.
63) Chapple RH, Tseng YJ, Hu T, Kitano A, Takeichi M, Hoegenauer KA, Nakada D. Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis. Blood Adv 2018; 2(11): 1220-1230.
64) Sawen P, Eldeeb M, Erlandsson E, Kristiansen TA, Laterza C, Kokaia Z, Karlssonb G, Yuan J, Soneji S, Mandal PK, Rossi DJ, Bryder D, Murine HSCs contribute actively to native hematopoiesis but with reduced differentiation capacity upon aging. Elife 2018; 7: e41258.
65) Biasco L, Pellin D, Scala S, Dionisio F, Basso-Ricci L, Leonardelli L,Scaramuzza S, Baricordi C, Ferrua F, Cicalese MP, et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell 2016; 19(1): 107-119.
66) Scala S, Basso-Ricci L, Dionisio F, Pellin D, Giannelli S, Salerio FA, Leonardelli L, Cicalese MP, Ferrua F, Aiuti A, Biasco L. Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nat Med 2018; 24(11): 1683-1690.
67) Lu R, Neff NF, Quake SR, Weissman IL. Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding. Nat Biotechnol 2011; 29(10): 928-933.
68) Lu R, Czechowicz A, Seita J, Jiang D, Weissman IL. Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo. Proc Natl Acad Sci USA 2019; 116(4): 1447-1456.
69) Koelle S, Espinoza DA, Wu C, Xu J, Lu R, Li B, Donahue RE, Dunbar CE. Quantitative stability of hematopoietic stem and progenitor cell clonal output in rhesus macaques receiving transplants. Blood 2017; 129(11): 1448-1457.
70) Six E, Guilloux A, Denis A, Lecoules A, Magnami A, Vilette R, Male F, Cagnard N, Delville M, Caccavelli L, et al. Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs. Blood 2000; 135(15): 1219-1231.
71) Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, Hegland J, Kamani N, Kernan NA, King R, Ratanatharathorn V, Weidorf D, Confer DL. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001; 98(7): 2043-2051.
72) Kollman C, Spellman SR, Zhang MJ, Hassebroek A, Anasetti C, Antin JH, Champlin RE, Confer DL, DiPersio JF, Fernandez-Vina M, et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood 2016; 127(2): 260-267.
73) DeZern AE, Franklin C, Tsai HL, Imus PH, Cooke KR, Varadhan R, Jones RJ. Relationship of donor age and relationship to outcomes of haploidentical transplantation with posttransplant cyclophosphamide. Blood Adv 2021; 5(5): 1360-1368.
74) Poletto E, Colella P, Pimentel Vera LN, Khan S, Tomatsu S, Baldo G, Gomez-Ospina N. Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation. Mol Ther: Methods & Clinical Dev 2022; in press.
75) Marktel S, Scaramuzza S, Cicalese MP, Giglio F, Galimberti S, Lidonnici MR, Calbi V, Assanelli A, Bernardo ME, Rossi C, et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent β-thalassemia. Nat Med 2019; 25(2): 234-241.
76) Felker S, Shrestha A, Bailey J, Pillis DM, Siniard D, Malik P. Differential CXCR4 expression on hematopoietic progenitor cells versus stem cells directs homing and engraftment. JCI Insight 2022; 7(9): e151847.
77) Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ. Cell intrinsuic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA 2005; 102(26): 9194-9199.
78) Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoieijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 2007; 447(7145): 725-729.
79) Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 2007; 5(8): e201.
80) Ganuza M, Hall T, Finkelstein D, Wang YD, Chabot A, Kang G, Wu B, Wu G, McKinney-Freeman S. The global clonal complexity of the murine blood system declines throughout life and after serial transplantation. Blood 2019; 133(18): 1927-1942.
81) Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, Schrier SL, Weissman IL. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci USA 2011; 108(50): 20012-20017.
82) Nilsson AR, Soneji S, Adolfsson S, Bryder D. Human and murine hematopoietic stem cell aging is associataed with functional impairments and intrinsic megakaryocytic/erythroid bias. PLoS ONE 2016; 11(7): e158369.
83) Kuranda K, Vargaftig J, de la Rochere P, Dosquet C, Charron D, Bardin F, Tonnelle C, Goodhardt M. Age-related changes in human hematopoietic stem progenitor cells. Aging Cell 2011; 10(3): 542-546.
84) Kowalczyk M, Tirosh I, Hechi D, Rao TN, Dixit A, Haas BJ, Schneider RK, Wagers AJ, Ebert BL, Regev A. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. Genome Res 2015; 25(12): 1860-1872.
85) Salic A, Mitchison TJ. A chemical method for fast and sensitive detection of DNA synthesis. Proc Natl Acad Sci USA 2008; 105(7): 2415-2420.
86) Kovtonyuk LV, Ashcroft P, Spaltro G, Tata NR, Skoda RC, Bonhoeffer S, Manz MG. Hematopoietic stem cells increase quiescence during aging. Blood 2019; 134(suppl.1): 2484.
87) Florian MC, Dorr K, Niebel A, Daira D, Schrezenmeier H, Rojewski M, Filippi MD, Hasenberg A, Gunzer M, Scharffetter-Kochanek K, Zheng Y, Geiger H. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stam Cell 2012; 10(5): 520-530.
88) Florian MC, Klose M, Sacma M, Jablanovic J, Kundson L, Nattamai KJ, Marks G, Vollmer A, Soller K, Sakk V, et al. Aging alters the epigenetic asymmetry of HSC division. PLos Biology 2018; 16(9): e2003389.
89) Amoah A, Keller A, Emini R, Hoenicka M, Libelold A, Vollmer A, Eiwen K, Soller K, Sakk V, Zheng Y, Florian C, Geiger H. Aging of human hematopoietic stem cells is linked to changes in Cdc42 activity. Haematologica 2022; 107(2): 393-402.
90) Schmacher B, Pathof J, Vijg J, Hoeimakers J. The central role of DNA damage in the ageing process. Nature 2021; 592(7856): 695-703.
91) Mohrin M, Bouorke E, Alexander D, Warr MR, Barry-Holson K, LeBeau MM, Morrison CG, Passagué E. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 2010; 7(2): 174-185.
92) Beerman I, Seitu J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 2014; 15(1): 37-50.
93) Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, Alvarez S, Diolaiti ME, Ugarte F, Forsberg EC, et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 2014; 512(7513): 198-202.
94) Walter D, Lier A, Geiselhart A, Thalheimer FB, Huntscha S, Sobotta MC, Mehrle B, Brocks D, Bayindir I, Kraschutnig P, et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature 2015; 520(7548): 549-552.
95) Pan Y, Zuo H, Wen F, Huang F, Zhu Y, Cao L, Sha QQ, Li Y, Zhang H, ShiM, et al. HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses. Leukemia 2022; 36(4): 1123-1131.
96) Heylmann D, Ponath V, Kindler T, Kaina B. Comparison of DAN repair and radiosensitivity of different blood cell populations. Scient Rep 2021; 11(11): 2478.
97) Biechonski S, Olender L, Zipin-Roitman A, Yassin M, Aqaqe N, Marcu-Malina V, Rall-Scharpf M, Trottier M, Meyn MS, Wiesmuller L, Beider K, Raz Y, Grisaru D, Nagler A, Milyavsky M. Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation. Scient Rep 2018; 8(1): 6071.
98) Yizhak K, Aguet F, Kim J, Hess J, Kubler K, Grimsby J, Frazer R, Zhang H, Haradhvaia NJ, Rosebrock D, Livitz D, Li X, Arich-Landkof E, Shoresh N, Stewart C, Segrè AV, Branton PA, Polak P, Ardle K, Getz G. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 2019; 364(6444): eaaw0726.
99) Milholland B, Dong X, Zhang L, Hao X, Vijg J. Differences between germline and somatic mutation rates in human and mice. Nat Commun 2017; 8(5): 15183.
100) Lee-Six H, Oebro NF, Shepherd MS, Grossmann S, Dawson K, Belmonte M, Osborne RJ, Huntlky B, Martincorena I, Anderson E, O’Neill L, Streatton MR, Laurent E, Green AR, Kent DG, Campbell PJ. Population dynamics of normal human blood inferred from somatic mutations. Nature 2018; 561: 473-478.
101) Osorio FG, Rosendahl Huber A, Oka R, VerheulnM, Patel SH, Hasaart K, de la Fonteijne L, Varela I, Camargo FD, van Boxtel R. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. Cell Rep 2018; 25(11): 2308-2316.
102) Brandsma AM, Bertrums E, van Rooismalen MJ, Hofman DA, Oka R, Verheulen M, Manders F, Ubels J, Bbelderbos ME, van Boxtel R. Mutation signatures of pediatric acute myeloid leukemia and normal blood progenitors associated with differential patient outcomes. Blood Cancer Discov 2021; 2(9): 484-499.
103) Mura F, Degasperi A, Nadeu F, Leongamornlert D, Davies H, Moore L, Royo R, Ziccheddu B, Puente XS, Avet-Loiseau, H, Campbell, PJ, Nik-Zainal S, Campo E, Munshi N, Bolli N. A practical guide for mutational signature analysis in haematological malignancies. Nat Commun 2019; 10: 2969.
104) Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Ng AWT, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstromn EN, Islam A, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V, PCAWG Mutational Signatures Woking Group, Getz G, Rozen SG, Startton MR, PCAWG Consortium. The repertoire of mutational signatures in humanb cancer. Nature 2020; 578: 94-101.
105) Vijg J, Dong X. Pathogenic mechanisms of somatic mutation and genome mosaicism in aging. Cell 2020; 182: 12-23.
106) Mustjoki S, Young NS. Somatic mutations in “benign” disease. N Engl J Med 2021; 384(21): 2039-2052.
107) Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126(1): 9-16.
108) Busque L, Patel JP, Figueroa M, Vasanthakumar A, Provost S, Hamilou Z, Mollica L, Li J, Viale A, Heguy A, Hassimi M, Socci N, Bhatt PK, Gonen M, Mason CE, Melnick A, Godley LA, Brennan C, Abdel-Wahab O, Levine RL. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 2012; 44: 1179-1181.
109) Genovese G, Kahler AK, Handsaker RE, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. New England J. Med. 2014; 371: 2477-2487.
110) Xie M, Lu C, Wang J, Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 2014; 20: 1472-1478.
111) Jaiswal S, Fontanillas P, Flannick J, Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 2014; 371: 2488-2498.
112) McKerrell T, Park N, Moreno T, Grove CS, Postingl H,Stephens J, Understanding Society Scientific Group, Crawley C, Craig J, Scoot MA, Hodkinson C, Baxter J. Rad R, Forsyth DR, Quail MA, Zeggini E, Ouwehand W, Varela I, Vassiliou GS. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015; 10(3): 1239-1245.
113) Buscarlet M, Provost S, Zada YF, Barhdadi A, Bourgoin V, Lépine G, Mollica L, Szuber N, Dubé MP, Busque L. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 2017; 130(6): 753-762.
114) Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 2016; 7: 12484.
115) Arends CM, Galan-Sousa J, Hoyer K, Chan W, Jager M, Yoshida K, Seeman R, Noerenberg D, Waldhueter N, Fleisher-Notter H, Christen F, Schmitt CA, Dorken B, Pelzer U, Sinn M, Zemojtel T, Ogawa S, Mardan S, Schreiber A, Kunitz A, Kruger U, Bullinger L, Mylonas E, Frick M, Damm F. Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. Leukemia 2018; 32(9): 1908-1919.
116) Zink F, Stacey SN, Nordahl GL, Frigge ML, agnusson OT, Jondottir I, Thorgeirsson TE, Sigursson A, Gudjonsson SA, Gudmundsson J, Jonasson JN, Tryggvadottir L, Jonsson T, Helagason A, Gylfason A, Sulem P, Rafnar T, Thorsteinsdottir U, Gudbjartsson DF, Masson G, Kong A, Stefansson K. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 2017; 130(6): 742-752.
117) Van Zeventer IA, Salzbrunn JB, de Graaf AO, van der Reijden BA, Boezen HM, Vonk JM, van der Harst P, Schuringa JJ, Jansen JH, Huls G. Prevalence, predictors, and outcomes of clonal hematopoiesis in individuals aged ≥80 years. Blood Adv. 2021; 5(8): 2115-2122.
118) Rossi M, Meggendorfer M, Zampini M, Tettamanti M, Riva E, Travaglino E, Bersanelli M, Mandelli S, Galbussera AA, osca E, et al. Clinical relevance of clonal hemopoiesis in persons aged ≥80 years. Blood 2021; 138(21): 2093-2105.
119) Kar SP. Quiros PM, Gu M, Jiang T, Lagdon R, Iyer V, Barcena C, Vijayabaskar MS, Fabre MA, Carter P, Burgess S, Vassiliou GS. Genome-wide analyses of 200,453 individuals yeld new insights into the causes and consequences of clonal hematopoiesis. BioRxIV 2022; 10.1101/2022.01.06.22268846.
120) Fabre MA, De Almeida JG, Fiorillo E, Mitchell E, Damaskou A, Rak J, Orrù V, Maronglu M, Vijayabaskar MS, Baxter J, et al. The longitudinal dynamics and natural history of clonal hematopoiesis. BioRxIV 10.1101/2021.
121) Pich O, Reyes-Salazar I, Gonzalez-Perez A, Lopez-Bigas N. Discovering the drivers of clonal hematopoiesis. BioRxIV 2020, 10.22.350140.
122) Beauchamp EM, Leventhal M, Bernard E, Hoppe ER, Todisco G, Creignou M, Galli A, Castellano CA, McConkey M, Tarun A, et al. ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. Blood Cancer Discov 2021, 2 :500-517.
123) Poon G, Watson CJ, Fisher DS, Blundell JR. Synonymous mutations reveal genome-wide levels of positive selection in healthy tissues. Nat Genet 2021; 53(11): 1597-1605.
124) Mitchell E, Chapmen MS, Williams N, Dawson K, Mende N, Caldferbank EF, Jung H, Mitchell T, Coorens T, Spencer D, et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature 2022; 606(7913): 343-350.
125) Abascal F, Harvey L, Mitchell E, Lawson A, Lensing S, Ellis P, Russell A, Alcantara R, Baez-Ortega A, Wang Y, et al. Somatic mutation landscapes at single-molecule resolution. Nature 2021; 593(7859): 405-410.
126) Wong WH, Tong S, Druley TE. Error-corre3cted sequencing of cord bloods identifies pediatric AMNL associated clonal hematopoiesis. Blood 2017; 130, suppl.1, 2687.
127) Hasaart K, Manders F, van der Hoorn ML, Verheul M, Popolonski T, Kruijk E, Chuva de Lopes S, van Boxtel R. Mutation accumulation and developmental lineages in normal and Down syndrome human fetal hematopoiesis. Scient Rep 2020; 10: 12991.
128) Chapman MS, Ranzoni AM, Myers B, Williams N, Coorens T, Mitchell E, Butler T, Dawson K, Hooks Y, Moore L, Nangalia J, Robinson PS, Yoshida K, Hook E, Campbell PJ, Cvejic A. Lineage tracing of human development through somatic mutations. Nature 2021; 595: 85-90.
129) Hansen JW, Pedersen DA, Larsen LA, Husby S, Clemmensen SB, Hjelmborg J, Favero F, Weischenfeldt J, Christensen K, Gronbaek K. Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality. Blood 2020; 135: 261-268.
130) Niroula A, Sekar A, Murakami MA, Trinder M, Agrawal M, Wong WJ, Bick AG, Uddin M, Gibson CJ, Griffin GK, Honigberg MC, Sekavat SM, Parachuri K, Natarajan P, Ebert BL. Distinction of lymphoid and myeloid clonal hematopoiesis. Nature Medicine 2021; in press.
131) Challen GA, Goodell MA. Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 2020; 136: 1590-1598.
132) Chin DWL, Yoshizato T, Culleton SV, Grasso F, Barbachowska M, Ogawa S, Jacobsen SEW, Woll PS. Aged healthy mice acquire clonal hematopoietic mutations. Blood 2022; 139(4): 629-634.
133) Christen F, Hablesreiter R, Hoyer K, Hennch C, Maluck-Bottcher A, Segler A, Madadi A, Frick M, Bullinger L, Briest F, Damm F. Modeling clonal hematopoiesis in umbilical cord blood cells by CRISPR/Cas9. Leukemia 2022; 36(4): 1102-1110.
134) Boettcher S, Wilk CM, Singer J, Beier F, Burcklen E, Biesel C, Ventura Ferreira MS, Gourri E, Gassner C, Frey BM, Schanz U, Skoda RC, Ebert BL, Brummendorf TH, Beerenwinkel, N, Manz MG. Clonal hematopoiesis in donors and long-term survivors of related allogeneic hematopoietic stem cell transplantation. Blood 2020; 135(18): 1548-1559.
135) Wong WH, Bhatt S, Trinkaus K, Pusic I, Elliott K, Mahajan N, Wan F, Switzer GE, Confer DL, DiPersio J, Pulsipher MA, Shah NN, Seses J, Bystry A, Blundell JR, Shaw BE, Druley TE. Enfraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cells transplantation. Sci. Transl Med 2020; 12(526): doi:10.1126.
136) Heini AD, Porret N, Zenhaeusen R, Winkler A, Bacher U, Pabst T. Clonal hematopoiesis after autologous stem cell transplantation does not confer adverse prognosis in patients with AML. Cancers 2021; 13: 3190.
137) Oran B, Champlin RE, Wang F, Tanaka T, Saliba RM, Al-Atrash G, Garcia-Manero G, Kantarjian H, Cao K, Shpall EJ, Alousi AM, Melita RS, Popat U, Futreal U, Takahashi K. Donor clonal hematopoiesis increases graft versus host disease after matched sibling transplantation. Leukemia 2021; in press.
138) Nevejan L, Nollet F, Devos H, Vynck M, Van Vlieberghe P, Tajdar M, Lodewyck T, Selleslag D. Malignant progression of donor-engrafted clonal hematopoiesis in sibling recipients after stem cell transplantation. Blood Adv 2020; 4(22): 5631-5634.
139) Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, Ling H, Hetrick KN, Pugh EW, Amos C, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 2012; 44(6): 642-650.
140) Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, Hutchinson A, Deng X, Liu C, Horner MJ, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 2012; 44(6): 651-658.
141) Loh PR, Genovese G, Handsaker RE, Finucane HK, Reshf JA, Palamara PF, Birmann BM, Talkowski ME, Bakhoum SF, McCarroll SA, Price AL. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 2018; 559: 350-355.
142) Terao C, Suzuki A, Mmomozawa Y, Akiytama M, Ishigaki K, Yamamoto K, Matsuda K, Murakami Y, McCarroll SA, Kubo M, Loh PR, Kamatami Y. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 2020; 584: 130-134.
143) Zekavat SM, Lin SH, Bick AG, Liu A, Paruchuri K, Wang C, Uddin M, Ye Y, Yu Z, Liu X, Kamatani Y, et al. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nat Med 2021; 27(6): 1012-1024.
144) Thompson DJ, Genovese G, Halvardson J, Ulirsch JC, Wright DJ, Terao C. Genetic predisposition to mosaic Y chromosome loss in blood. Nature 2019; 575: 652-657.
145) Ljungstrom V, Mattisson J, Halvardson J, Pandzic T, Davies H Rychlicka-Buniowska E, Danielsson M, Lacaze P, Cavelier L, Dumanski JP, Baliakis P, Forsberg LA. Loss of Y and clonal hematopoiesis in blood-two sides of the same coin? Leukemia 2021; in press.
146) Ouseph MM, Hasserjian RPDal Cin P, Lovitch SB, Steensma DP, Nardi V, Weinberg OK. Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells. Haematologica 2021; 106(2): 555-564.
147) Lin SH, Loftfield E, Sampson JN, Zhou W, Yeager M, Freedman ND, Chanock SJ, Machiela MJ. Mosaic chromosome Y loss is associated with alterations in blood cell counts in the UK Biobank men. Scient Rep. 2020; 10: 3655.
148) Saiki R, Momozawa Y, Nannya Y, Nakagawa MM, Ochi Y, Yoshizato T, Terao C, Kuroda Y, Shiraishi Y, Chiba K, Tanaka H, Niida A, Imoto S, Matsuda K, Morisaki T, Murakami Y, Kamatani Y, Matsuda S, Kubo M, Miyano S, Makishima H, Ogawa S. Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis. Nature Med. 2021; 27(7): 1239-1249.
149) Brown DW, Cato LD, Zhao Y, Nandakumar SK, Bao EL, Rehling T, Song L, Yu K, Chanock SJ, Perry J, Sankaran VG, Machiela MJ. Shared and distinct genetic etiologies for different types of clonal hematopoiesis. BioRxiv 2022; in press.
150) Van Zeventer IA, de Graaf A, Koorenhof-Scheele TN, van der Reijden BA, van der Klauw MM, Dinmohamed AG, Diepstra A, Schuringa JJ, Malcovati L, Huls G, Jansen JH. Monocytosis and its association with clonal hematopoiesis in community-dwelling individuals. Blood Adv 2022; in press.
151) Silver AJ, Bick AG, Savona MR. Germline risk of clonal haematopoiesis. Nat. Rev Genet. 2021; 22(9): 603-617.
152) Bick AG, Weinstock JS, Nandakumar SK, Fulco CP, Bao EL, Zekavat SM, Szeto MD, Liao X, Leventhal MJ, Nasser J, et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 2020; 586: 763-768.
153) Cohen Aubart F, Roos-Weil D, Armand M, Marceau-Renault A, Emile JF, Duployez N, Charlotte F, Poulain S, Lhote R, Helias-Rodzewicz Z, Della-Valle V, Bernard O, Maloum K, Ngueyen-Khac F, Donadieu J, Amoura Z, Abdel-Wahab O, Heroche J. High frequency of clonal hematopoiesis in Erdheim-Chester disease. Blood 2021; 137(4): 485-492.
154) Ferris MA, Smith AM, Heath SE, Duncavage EJ, Oberley MJ, Freyer D, Wynn R, Douzgou S, Maris JM, Reilly AF, Wu M, Choo F, Fiets RB, Koene S, Spencer DH, Miller CA, Shinawi M, Ley TJ. DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. Blood 2022; 139(3): 461-464.
155) Smith AM, LaValle TA, Shinawi M, Ramakrishan SM, Abel HJ, Hill CA, Kirkland NM, Rettig MP, Helton NM, Heath SE, Ferraro F, Chen DY, Adak S, Semenkovich CF, Christian DL, Martin JR, Gabel HW, Miller CA, Ley TJ. Functional and epigenetic phenotypes of humans and mice with DNMT3A overgrowth syndrome. Nat Commun 2021; 12: 4549.
156) Tovy A, Rosas C, Gaikwad AS, Medrano G, Zhang L, Reyes JR, Huang YH, Arakawa T, Kurtz K, Conneely SE, Guzman AG, Aguilar R, Gao A, Chen CW, Kim JJ, Carter MT, Lasa-Aranzasti A, Valenzuela I, Maldergem LV, Brunetti L, Hicks MJ, Marcogliese AN, Goodell MA, Rau RE. Perturbed hematopoiesis in individuals with germile DNMT3A overgrowth Tatton-Brown-Rahman syndrome. Haematologica 2022, 107(4): 887-898.
157) Xia J, Miller CA, Baty J, Ramesh A, Jotte M, Fulton RS, Vogel TP, Cooper MA, Walcovich KJ, Maaaaakarayan V, Bolyard AA, Dinauer MC, Wilson DB, Vlachos A, myers KC, Rothbaum RJ, Bertuch AA, Dale DC, Shimamura A, Boxer LA, Link DC. Somatic mutations and clonal hematopoiesis in congenital neutropenia. Blood 2018; 131(4): 408-416.
158) Kennedy AL, Myers KC, Bowman J, Gibson CJ, Camarda ND, Furutani E, Muscato GM, Klein RH, Ballotti K, Liu S, et al. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun 2021; 12: 1334.
159) Furutani E, Liu S, Galvin A, Steltz S, Malsch MM, Loveless SK, Mount L, Larson JH, Queenan K, Bertuch AA, et al. Hematologic complications with age in Schwachman-Diamond syndrome. Blood Adv 2022; 6(1): 297-306.
160) Narumi S, Amano N, Ishii T, Katumata N, Muroya K, Adachi M, Toyoshima K, Tanaka Y, Fukuzawa R, Miyako K, et al. SAMD9 mutations cause a novel mulisystem dosorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat. Genet. 2016; 48(7): 792-797.
161) Tesi B, Daudsson J, Voss M, Rahikkala E, Holmes TD, Chang S, Komulainen-Ebrahim J, Gorcenco S, Rundberg Nilsson A, Ripperberg T, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood 2017; 129(16): 2266-2279.
162) Wong JC, Bryant V, Lamprecht T, Ma J, Walsh M, Schwartz J, del pilar Alzamora M, Mullighan CC, Loh ML, Ribeiro R, et al. Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes. JCI Insight 2018; 3(14): e121086.
163) Schwartz JR, Ma J, Lamprecht T, Walsh M, Wang S, Bryany V, Song G, Wu G, Easton J, Kesserwan C, Nichols KE, Mullighan CG, Ribeiro RC, Klco JM. The genomic lanscape of pediatric myelodysplastic syndromes. Nat Commun 2017; 8: 1557.
164) Sahoo SS, Pastor VB, Goodings C, Voss RK, Kozyra RJ, Szvetnik A, Noellke P, Dworzak M, Stary J, Locatelli F, et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SMD9/SAMD9L syndromes. Nat Med 2021; 27(10): 1806-1817.
165) Thomas ME, Abdelhamed S, Hiltenbrand R, Schwartz JR, Sakurada SM, Walsh M, Song G, Ma J, Pruett-Miller SM, Klco JM. Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SMAD9L impair multiple pathways in primary hematopoietic cells. Leukemia 2021; 35(1): 3232-3244.
166) Jasra S, Giricz O, Zeig-Owens R, Pradhan K, Goldfarb DG, Barreto-Galvez A, Silver AJ, Chen J, Sahu S, Gordon-Mitchell S, et al. High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster. Nat Med 2022; 28(3): 468-471.
167) Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, Hyman DM, Solit DB, Robson ME, Baselga J, Arcila ME, Ladanyi M, Tallman MS, Levine RL, Berger MF. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 2017; 21(9): 374-382.
168) Ptashkin RN, Mandelker DL, Coombs CC, Bolton K, Yelskaya Z, Hyman DM, Solit DB, Baselga J, Arcila ME, Ladanyi M, et al. Prevalence of clonal hematopoiesis mutations in tumor-only clinical genomic profiling of solid tumors. JAMA Oncol. 2028; 4(11): 1589-1593.
169) Coombs CC, Gillis NK, Tan X, Berg JS, Ball M, Balasis ME, Montgomery ND, Bolton KL, Parker JS, Mesa TE, Yoder SJ, Hayward M, Patel NM, Richards KL, Walko CM, Knepper TC, Earp III HS, Levine RL, Papaemmanuil E, Zehir A, Hayes DN, Padron E. Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays. Clin Cancer Res 2018; 24(23): 5918-5924.
170) Severson EA, Riedinger GM, Connelly CF, Vergilio CA, Golfinger M, Ramkisson S, Frampton GM, Ross JS, Fratella-Calabrese A, Gay L, Ali S, Miller V, Elvin J, Hadigol M, Hirshfield KM, Rodriguez-Rodriguez L, Ganesan S, Khiabanian H. Detection of clonal hematopoiesis of indeterminate potential in clinical sequencing of solid tumor specimens. Blood 2018; 131(22): 2501-2505.
171) Gao T, Ptashkin R, Bolton KL,Sirenko M, Fong C, Spitzer B, Menghrajani K, Arango Ossa JE, Zhou Y, Bernard E, Levine M, Medina Martinez JS, Zhang Y, Franch-Esposito S, Patel M, Braunstein LZ, Kelly D, Yabe M, Benayed R, Caltabellotta NM, Philip J, Paraiso E, Mantha S, Solit DB, Diaz LA, Berger MF, Klimek V, Levine RL, Zehir A, Devlin SM, Papaemmanuil E. Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis.
172) McNerney ME, Godley LA, Le Beau MM. Therapy-related myeloid neoplasm: when genetics and environment collide. Nat. Rev. Cancer 2017; 17(9): 513-527.
173) Tiruneh T, Enawgaw B, Shiferaw E. Genetic pathway in the pathogenesis of therapy-related myeloid neoplasms: a literature review. Oncol Ther 2020; 8: 45-57.
174) Pich T, Muinos F, Lolkema MP, Steeghs N, Gonzalez-Perez A, Lopez-Bigas N. The mutational fottprints of cancer therapies. Nature Genet 2019; 51: 1732-1740.
175) Pich O, Bullich-Cortes A, Muinos F, Pratcorona M, Gonzalez-Perez A, Lopez-Bigas N. The evolution of hematopoietic cells under cancer therapy. Nat Commun 2021; 12: 4803.
176) Diamond B, Zicheddu B, Maclachlan K, Taylor J, Boyle E, Ossa JA, Jahn J, Affer M, Totiger TM, Coffey D, et al. Chemotheray signatures map evolution of therapy-related myeloid neoplasms. BioRxiv 2022; in press.
177) Tariq H, Stonim LB, Coty Fattal Z, Alikan MB, Segal J, Gurbuxani S, Helenowski IB, Zhang H, Sukhanova M, Lu X, Altman JK, Chen QC, Bahdad A. Therapy-related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype. Br J Haematol 2022; in press.
178) Wong TN, Miller CA, Jotte M, Bagegni N, Baty JD, Schmidt AP, Cashen AF, Duncavage DJ, Helton NM, Fiala M, Fulton RS, Heath SE, Janke M, Luber K, Westervelt P, Vij R, DiPersio JF, Welch JS, Graubert TA, Walter MJ, Ley TJ, Link DC. Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat. Commun. 2018; 9(1): 455.
179) Husby S, Favero F, Nielsen C, Sorensen BS, Baech J, Grell K, Hansen JW, Rodriguez-Gonzalez FG, Haastrup EK, Fischer-Nielsen A, et al. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study. Leukemia 2020; 34: 3256-3268.
180) Gibson CJ, Lindslay RC, Tchekmedyan V, Mar BG, Shi J, Jaiswal S, Bosworth A, Francosco L, He J, Bansal A, Morgan EA, Lacasce AS, Preedman AS, Fisher DC, Jacobsen E, Armand P, Alyea EP, Koreth J, Ho V, Soiffer RJ, Antin JH, Ritz J, Nikiforow S, Forman SJ, Michor F, Neuberg D, Bhatia R, Bhatia S, Ebert BL. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell trasnplantation for lymphoma. J. Clin. Oncol. 2017; 35( 14): 1598-1605.
181) Eskelund CW, Husby S, Favero F, Wirenfeldt Klausen T, Rodriguez-Gonzalez FG, Kolstadt A, Pedersen LB, Raty RK, Geisler CH, Jerkeman M, Weischenfeldt J, Grobaek K. Clonal hematopoiesis evolves from pretreatment clones and stabilizes after end of chemotherapy in patients with MCL. Blood 2020; 135: 2000-2003.
182) Venanzi A, Marra A, Schiavoni G, Millner SG, Limongello R, Santi A, Pettirossi V, Ultimo S, Tasselli L, Puccairini A, et al. Dissecting clonal hematopoiesis in tissues of patients with classic Hodgkin lymphoma. Blood Cancer Discov 2021; 2: 216-225.
183) Saini NY, Swoboda DM, Greenbaum U, Ma J, Patel RD, Devashish K, Das K, Tanner MR, Strati P, Nair R, et al. Clonal hematopoiesis is associated with increased risk of severe neurotoxicity in axicabtagene ciloleucel therapy of large B-cell lymphoma. Blood Cancer Discov 2022; in press.
184) Hatakeyama K, Hieda M, Semba Y, Moriyama S, Wang Y, Maeda T, Kato K, Miyamoto T, Akashi K, Kilkushige Y. TET2 clonal hematopoiesis is associated with anthracycline-induced cardiotoxicity in patients with lymphoma. JACC: Cardioncol 2022; 4: 141-143.
185) Lewis NE, Petrova-Drus K, Huet S, Epstein-Petersen ZD, Gao Q, Sigler AE, Baik J, Ozkaya N, Moskowitz AJ, Kuamr A, et al. Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasms. Blood Adv 2020; 4: 2291-2300.
186) Khanlari M, Yin CC, Takahashi K, Lachowiecz C, Tang G, Loghavi S, Bah I, Wang W, Konoplev S, Medeiros LJ, Pammaraju N, Khoury JD, Wang SA. Bone marrow clonal hematopoiesis is highly prevalent in blastic plasmocytoid dendritic cell neoplasms and frequently sharing a clonal origin in elderly patients. Leukemia 2022; 36: 1343-1350.
187) Mouhieddine, TH, Sperling AS, Redd R, Park J, Leventhal M, Gibson CJ, Manier S, Nassar AH, Capelletti M, Huynh D, et al. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant. Nature Commun 2020; 11: 2996.
188) Maia C, Puig N, Cedena MT, Goicoechea I, Valdes-Mas R, Vazquez I, Chillon MC, Aguirre P, Sarvide S, Grazia-Aznarez FJ, et al. Biological and clinical significance of dysplatic hematopoiesis in patients with newly diagnosed multiple myeloma. Blood 2020; 25: 2375-2387.
189) Tahri S, Mouhieddine TH, Redd R, Lampe L, Nilsson KI, El-Khoury H, Su Nk, Nassar AH, Adib E, Bindra G, et al. Clonal hematopoiesis is associated with increased risk of progression or asymptomatic Waldenstrom macroglobulinemia. Blood Adv 2022; 6: 2230-2238.
190) Zajkowicz A, Butkiewicz D, Drosik A, Giglok M, Suwinski R, Rusin M. Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Brit J Cancer 2015; 112: 1114-1120.
191) Pharoah P, Song H, Dirks E, Intermaggio MP, Harrington P, Baynes C, Alsop K, Australian Ovarian Cancer Group, Bogdanova D, Cicek MS, et al. PPM1S mosaic truncating variants in ovarian cancer cases may be treatment-related somatic mutations. J. Natl. Cancer Inst. 2016; 108(3): djv347.
192) Swisher EM, Harrell M, Norquist BM, Walsh T, Brady M, Lee M, Hershberg R, Kalli KR, Lankes L, Konnick EQ, Pritchard CC, Monk BJ, Chan JK, Burger R, Kaufmann SH, Birerr MJ. Somatic mosaic mutations in PPM1D and TP 53 in the blood of women with ovarian carcinoma. JAMA Oncol. 2(3): 370-372.
193) Kahn JD, Miller PG, Silver AJ, Sellar RB, Bhatt S, Gibson C, McConkey M, Adams D, Mar B, Mertins P, Fereshetian S, Krug K, Zhu H, Letai A, Carr SA, Doench J, Jaiswal S, Ebert BL. PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells- Blood 2018; 132(11): 1095-1105.
194) Bolton KL, Ptashkin RN, Gao T, Braunstein L, Devlin SM, Kelly D, Patel M, Berthon A, Syed A, Yabe M, et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nature Genetics 2020; 52(11): 1219-1226.
195) Leone G, Pagano L, Ben-yehuda D, Voso MT. Therapy-related leukemia and myelodysplasia: susceptibility and incidence. Haematologica 2007; 92(10): 1389-1398.
196) Leone G, Fianchi K, Pagano L, Voso MT. Incidence and susceptibility to therapy-related myeloid neoplasms. Chem. Biol. Interact. 2010; 184(1-2): 39-45.
197) Leone G, Fianchi L, Voso MT. Therapy-related myeloid neoplasms. Curr. Opin. Oncology 2011; 23(6): 672-680.
198) Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, Lamprecht TL, Shen D, Hundai J, Fulton RS, Heath S, Baty JD, Klco JM, Ding L, Mardis ER, Westervelt P, DiPersio JF, Walter MJ, Graubert TA, Ley TJ, Druley T, Link DC, Wilson RK. The role of TP53 mutations in the origin and evolution of therapy-related AML. Nature 2015; 518(7540): 552-555.
199) Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K, Thompson E, Zhao L, Patel K, Neelapu S, Gumbs C, Bueso-Ramos C, DiNardo CD, Colla S, Ravandi F, Zhang J, Huang X, Wu X, Samaniego F, Garcia-Menero G, Futreal PA. Pre-leukemic clonal hematopoiesis and the risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 2017; 18(1): 100-111.
200) Gillis NK, Ball M, Zhang Q, Ma Z, Zhao YL, Yoder SJ, Balasis ME, Mesa TE, Saliman DA, Lancet JE, Kromokji RS, List AF, McLeod HL, Alsina DA, Baz R, Shaln KH, Rollison DE, Padron E. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017; 18(1): 112-121.
201) Kwan TT, Oza AM, Tinker AV, Ray-Coquard I, Oaknin A, Aghajanian C, Lorusso D, Colombo N, Dean A, Weberpals J, Severson E, Vo LT, Goble S, Maloney S, Harding T, Kaufmann SH, Ledermann JA, Coleman RL, McNeish IA, Lin KK, Swisher EM. Preexisting TP53-variant clonal hematopoiesis and risk of secondary myeloid neoplasms in patients with high-grade ovarian cancer treated with rucapirib. JAMA Oncol. 2021; e214664.
202) Khalife-Hachem S, Saleh K, Pasquier F, Willekens C, Taraby A, Antoun L, Grinda T, Castilla-Llorente C, Duchmann M, Quivoron C, Auger N, Saada V, Delaloge S, Leary A, Renneville A, Antony-Debre J, Rosselli F, De Botton S, Salviat F, Marzac C, Micol JB. Molecular landscape of therapy-related myeloid neoplasms in patients previously treated for gynecologic and breast cancer. HemaSphere 2021; 5(9): e632.
203) Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, Pigneux A, Wetzler M, Stuart RK, Erba HP, Damon LE, Powell BL, Lindeman N, Steensma DP, Wadleigh M, DeAngelo DJ, Neuberg D, Stone RM, Ebert BL. Acute myeloid ontogeny is defined by distinct somatic mutations. Blood 2015; 125(9): 1367-1376.
204) Coorens T, Collord G, Lu W, Mitchell E, Ijaz J, Roberts T, Oliver T, Burke A, Gattens M, Dickens E, Nangalia J, Tischkowitz M, Anderson J, Shlien A, Godfrey AL, Murray MJ, Behjati S. Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment. Blood 2021; 137(21): 2992-2997.
205) Chen S, Wang Q, Yu H, Capitano ML, Vermula S, Nabinger SC, Gao R, Yao C, Kobayashi M, Geng Z, Fahey A, Henley D, Liu SZ, Barajas S, Cai W, Wolf ER, Ramdas B, Cai Z, Gao H, Luo N, Sun Y, Wong TN, Link DC, Liu Y, Boswell HS, Mayo LD, Huang G, Kapur R, Yoder MC, Broxmeyer HE, Gao Z, Liu Y. Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway. Nature Commun 2019; 10: 5649.
206) Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N, Niemeyer E, Barda N, Zuzarte PC, Heister L, Sundaravadanam Y, et al. Prediction of acute myeloid leukemia risk in healthy individuals. Nature 2018; 559(7714): 400-404.
207) Desai P, Mencia-Trinchant N, Savenkov O, Simon MS, Cheang G, Lee S, Samuel M, Ritchie EK, Guzman ML, Ballman KV, Roboz GJ, Hassane DC. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nature Med. 24(7): 1015-1023.
208) Young AL, Tong RS, Birmann BM, Druley TE. Clonal hematopoiesis and risk of acute myeloid leukemia. Haematologica 2019; 104(12): 2410-2417.
209) Watson CJ, Papula A, Poon Y, Wong WH, Young AL, Druley TE, Fisher DS, Blundell JR. The evolutionary dynamics and fitness landscape of clonal haematopoiesis. Science 2020; 367(6485): 1449-1454.
210) Sill H, Zebisch A, Haase D. Acute myeloid leukemia and myelodysplastic syndromes with TP53 aberrations – a distinct stem cell disorder. Clin Cancer Res 2020; 26(20): 5304-5309.
211) Boettcher S, Miller PG, Sharma R, McConkey M, Leventhal M, Krivstov AV, Giacomelli AO, Wong W, Kim J, Chao S, Kurppa KJ, Yang X, Milenkowic K, Piccioni F, Root DE, Rucker FG, Flamand Y, Neuberg D, Lindsley RC, Janne PA, Hahn WC, Jacks T, Dohner H, Armstrong SA, Ebert BL. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science 2019; 365(6453): 599-604.
212) Zebisch A, Lai R, Muller M, Lind K, Kashofer K, Girschikofsky M, Fuchs D, Wolfler A, Geigl JB, Sill H. Acute myeloid leukemia with TP53 germ line mutations Blood 2016; 128(18): 2270-2272.
213) Stengel A, Kern W, Haferlach T, Meggendorfer M, Fasan A, Haferlach C. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. Leukemia 2017; 31(3): 705-711.
214) Prochazka K, Pregartner G, Rucker FG, Heltzer E, Pabst G, Wolfler A, Zerbish A, Berghold A, Dohner K, Sill H. Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. Haematologica 2018; 104(3): 516-523.
215) Goel S, Hall J, Pradhan K, Hirsch C, Przychodzen B, Shastri A, Mantzaris I, Janakiram M, Battini R, Kornblum N, Derman O, Gristman K, Al-Hadifh J, Wang Y, Halmos B, Steidl U, Macijewski JP, Braunschweig I, Verma A. High prevalence and allele burden-independent prognostic importance of p53 mutations in an inner-city MDS/AML cohort. Leukemia 2016; 30: 1793-1795.
216) Lal R, Lind K, Heitzer H, Ulz P, Aubell K, Kashofer K, Middeke JM, Thiede C, Schutz E, Rosenberger A, Hofer S, Felhauer B, Rinner B, Svendova V, Schimek MG, Rucker FG, Hoefler G, Dohner K, Zebisch A, Wolfler A, Sill H. Somatic TP53 mutations characterize preleukemic stem cells in acute myeloid leukemia. Blood 2017; 129(18): 2587-2591.
217) Pabst G, Lind K, Graf R, Zebisch A, Stolzel F, Dohner K, Heltzer E, Reinisch A, Sill H. TP53 mutated AML subclones exhibit engraftment in a humanized bone marrow ossicle mouse model. Ann Hematol 2020; 99: 653-655.
218) Quintas-Cardama A, Hu C, Qutub A, Qiu YH, Zhang X, Post SM, Zhang N, Coombes K, Kornblau SM. P53 pathway dysfunction is highly prelavent in acute myeloid leukemia independent of TP53 mutational status. Leukemia 2017; 31(6): 1296-1305.
219) Carvajal LA, Ben Neriah D, Senecal A, Bernard L, Tiruthuvanathan V, Yatsenko T, Narayanagari SR, Wheat JC, Todorova TI, Mitchell K, Kenworthy C, Guerlavis V, Annis DA, Bartholdy B, Will B, D’Anampa J, Mantzaris I, Alvado M, Singer RH, Coleman RA, Verma A, Steidl U. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Trans Med 2018; 10(436): eaao3003.
220) Yang M, Pan Z, Huang K, Busche G, Liu H, Gohring G, Rumpel R, Dittrich-Breiholz O, Talbot S, Scherr M, Chaturvedi A, Eder M, Skokowa J, Zhou J, Welte K, von Neurhoff N, Liu L, Ganser A, Li Z. A unique role of p53 haploinsufficiency or loss in the development of acute myeloid leukemia with FLT3-ITD mutation. Leukemia 2021; in press.
221) Ortmann CA, Dorsheimer L, Abou-El.Ardat K, Hoffrichter J, Assmus B, Bonig H, Scholz A, Pfeifer H, Martin H, Schmid T, Brune B, Scheich S, Steffen B, Riemann J, Hermann S, Dukat A, Bug G, Brandts CH, Wagner S, Serve H, Rieger MA. Functional dominance of CHIP-mutated hematopoietic stem cells in patients undergoing autologous transplantation. Cell Rep. 2019; 27(9): 2022-2028.
222) Soerensen JF, Aggerholm A, Kendrup GB, Hansen MC, Ewald IK, Bill M, Ebbesen LH, Rosenberg CA, Hokland P, Ludvigsen M, Roug AS. Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post-autologous stem cell transplantation. Blood Adv 2020; 10(4): 885-892.
223) Berger G, Kroeze LI, Koorenhof-Scheele TN, de Graaf AO, Yoshida K, Ueno H, Shiraishi Y, Miyano S, van den Berg E, Schepers H, van der Reijden BA, Ogawa S, Vellenga E, Jansen JH. Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT. Blood 2018; 131(16): 1846-1857.
224) Frick M, Chan W, Arends CM, Hablesreiter R, Halik A, Heuser M, Michonneau D, Blau O, Hoyer K, Christen F, et al. Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 2018; 36: 1-10.
225) Gibson CJ, Kim HT, Zhao L, Murdock M, Hambley B, Ogata A, Madero-Marroquin R, Wang S, Green L, Fleharty M, Dougan T, et al. Donor clonal hematopoiesis and recipient outcomes after transplantation. J Clin Oncol 2021; in press.
226) Gondek LP, Zheng G, Ghiaur G, DeZern AE, Matsui W, Yegnasubramanian S, Lin MT, Levis M, Eshleman JR, Varadhan R, Ticker N, Jones R, Gocke CD. Donor cell leukemia arising from clonal hematopoiesis after bone marrow transplantation. Leukemia 2016; 30(4): 1916-1920.
227) Herold S, Kuhn M, Bonin MV, Stange T, Platzbecker U, Radke J, Lange T, Sockel K, Gutsche K, Schetelig J, Rollig C, Schuster C, Roeder I, Dahl A, Mohr B, Serve H, Brandts C, Ahninger G, Bornhauser M, Thiede C. Donor cell leukemia: evidence for multiple preleukemic clones and parallel long term clonal evolution in donor and recipient. Leukemia 2017; 31(7): 1637-1640.
228) Gibson CJ, Kennedy JA, Nikiforow S, Kuo FC, Alyea EP, Ho, Ritz J, Soiffer R, Antin JH, Lindsley RC. Donor-engrafted CHIP is common among stem cell transplant recipients with unexplained cytopenias. Blood 2016; 130(1): 91-94.
229) Gibson CJ, Lindsley RC. Stem cell donors should not be screened for clonal hematopoiesis. Blood Adv 2020; 4(4): 789-792.
230) DeZern AE, Gondek LP. Stem cell donors should be screened for CHIP. Blood Adv 2020; 4(4): 784-788.
231) Valent P, Akin C, Arock M, Bock C, George TI, Galli SJ, Gotlib J, Haferlach T, Hoermann G, Hermine O, et al. Preposed terminology and classification of pre-malignant neoplastic conditions: a consensus proposal. EBioMedicine 2017; 26: 17-24.
232) Valent P, Kern W, Hoermann G, Milosevic Feenstra JD, Sotlar K, Pfeilstocker M, Germing U, Sperr WR, Reietr A, Wolf D, Arock M, Haferlach T, Horny HP. Clonal hematopoiesis with oncogenic potential (CHOP): separation from CHIP and roads to AML. Int Mol Sci 2019; 20: 789.
233) Cappelli LV, Meggendorfer M, Baer C, Nadarajah N, Hutter S, Jeromin S, Dicker F, Kem W, Haferlach T, Haferlach C, Hollein A. Indeterminate and oncogenic potential: CHIP and CHOP mutations in AML with NPM1 alteration. Leukemia 2021; in press.
234) Gurnari C, Fabiani E, Falconi G, Travaglini S, Ottone T, Cristiano A, Voso MT. From clonal hematopoiesis to therapy-related myeloid neoplasms: the silent way of cancer progression. Biology 2021; 10: 128.
235) DeZern AE, Malcovati L, Ebert BL. CHIP, CCUS, and other acronyms: definition, implications, and impact on practice. ASCO Educ Book 2019; 400-410.
236) Van Zeventer IA, de Graaf AO, van der Klauw MM, Vellenga E, van der Reijden BA, Schuringa JJ, Diepstra A, Malcovati L, Jansen JH, Huls G. Peripheral blood cytopenias in the aging general population and risk of incident hematological disease and mortality. Blood Adv 2021; 5(17): 3266-3278.
237) Kwok B, Hall JM, Witte JS, Xu Y, Reddy P, Lin K, Flamholz R, Dabbas B, Yung A, Al-Hadif J, Balmert E, Vaupei C, El Hader C, McGinnis MJ, Nahas SA, Kines J, Bejar R. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 2015; 126(21): 2355-2361.
238) Cargo CA, Rowbotham N, Evans PA, Barrans SL, Bowen DT, Crouch S, Jack AS. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood 2015; 126(21): 2362-2365.
239) Malcovati L, Galli A, Travaglino E, Ambaglio I, Rizzo E, Molteni E, Elena C, Ferretti VV, Catricalà S, Bono E, Todisco G, Bianchessi A, Rumi E, Zibellini S, Pietra D, Boveri E, Camaschella C, Toniolo D, Papaemmanuil E, Ogawa S, Cazzola M. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 2017; 129(25): 3371-3378.
240) Mikkelsen SU, Safavi S, Dimopoulos K, O’Rourke CJ, Andersen MK, Holm MS, Marcher CW, Andersen JB, Hansen JW, Grinboeck K. Structural aberrations are associated with poor survival in patients with clonal cytopenia of undetermined significance. Haematologica 2021; 106(6): 1762-1766.
241) Singh A, Mencia-Trinchant N, Griffiths EA, Altahan A, Swaminathan M, Gupta M, Gravina M, Tajammal R, Faber MG, Yan LB, et al. Mutant PPM1D- and TP53-driven hematopoiesis populates the hematopoietic compartment in response to peptide receptor radionuclide therapy. JCO Precis Oncol 2022; 6: e2100309.
242) Xie Z, Nanaa A, Saliba AN. Treatment outcome of clonal cytopenias of clonal cytopenias of undetermined significance: a single-institution retrospective study. Blood Cancer J 2021; 11(3): 43.
243) Jeong M, Park HJ, Celik H, Ostrander EL, Reyes JM, Guzman A, Rodriguez B, Lei Y, Lee Y, Ding L, et al. Loss of Dnmt3A immortalizes hematopoietic stem cells in vivo. Cell Rep 2018; 23(1): 1-10.
244) Loberg MA, Bell RK, Goodwin LO, Eudy E, Miles LA, SanMiguel JM, Young K, Bergstrom DE, Levine R, Schneider RK, Trowbridge JJ. Sequential inducible mouse models reveal that Nmp1 mutation causes malignant transformation of Dnmt3A-mutant clonal hematopoiesis. Leukemia 2019; 33(7): 1635-1649.
245) SanMiguel JM, Eudy E, Loberg MA, Miles LA, Steams T, Mistry JJ, Rauh MJ, Levine RL, Trowbridge JJ. Cell origin-dependent cooperativity of mutant Dnmt3A and Npm1 in clonal hematopoiesis and myeloid malignancy. Blood Adv 2022; 6(12): 3666-3677.
246) Kim PG, Niroula A, Shkolnik V, McConkey M, Lin AE, Stabicki M, Kemp JP, Bick A, Gibson CJ, Griffin G, et al. Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. 2021; 218(12): e20211872.
247) Huang YH, Chen CW, Sundaramurthy V, Stabicki M, Hao D, Watson CJ, Tovy A, Reyes JM, Dakhova O, Grovetti BR, et al. Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor. Cancer Discov 2022; 12: 220-235.
248) Smith AM, Verdoni AM, Abel HJ, Chen DY, Ketkar S, Leight ER, Miller CA, Ley TJ. Somatic Dnmt3a inactivation leads to slow, canonical DNA methylation loss in murine hematopoietic cells. iScience 2022; 25: 104004.
249) Nam AS, Dusaj N, Izzo F, Murali R, Myers RM, Mouhieddine T, Sotelo J, Benbarche S, Waarts M, Gaiti F, et al. Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation. BioRxiv 2022; 10.1101/2022.01.14.476225.
250) Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid differentiation. Cancer Cell 2011; 20(1): 11-24.
251) Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M. Detection of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 2011; 118(17): 4509-4518.
252) Ito K, Lee J, Chrysanthou S, Zhao Y, Josephs K, Sato H, Teruya-Feldstein J, Zheng D, Dawlaty MM, Ito K. Non-catalytic role of Tet2 are essential to regulate hematopoietic stem and progenitor cell homeostasis. Cell Rep 2019; 28(10): 1480-2490.
253) Nakauchi Y, Azizi A, Thomas D, Corces MR, Reisch A, Sharma R, Hernandez DC, Kohnke T, Karigane D, Fan A, et al. The cell type specific 5hmC landscape and dynamics of healthy hematopoiesis and TET2-mutant pre-leukemia. Blood Cancer Discov 2022; in press.
254) Tulstrup M, Soerensen M, Werner Hansen J, Gillberg L, Needhamsen M, Kaastrup K, Helin K, Christensen K, Weischenfeldt J, Gronbaeck K. TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis. Nature Commun 2021; 2:6061.
255) Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu T, Hricik T, Ndiaye-Lobry D, Lafave LM, et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med 2013; 210: 2641-2659.
256) Wang J, Li Z, He Y, Pan F, Chen S, Rhodes S, Nguyen L, Yuan J, Jiang L, Yang X, et al. Loss of Asxl1 leads to myelodysplastic syndrome-like syndrome. Blood 2014; 123: 541-553.
257) Inoue DJ, Kitaura J, Togami K, Nishimura K, Enomoto Y, Uchida T, Kagiyama Y, Kawabata KC, Nakahara F, Izawa K, et al. Myelodysplastic syndromes are induced by histone methylation-altering ASXL1 mutations. J Clin Invest 2013; 123: 4627-4640.
258) Nagase R, Inoue D, Pastore A, Fujino T, Hou HN, Yamasaki N, Goyama S, Saika M, Kanai A, Sera Y, et al. Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation. J Exp Med 2018; 215(6): 1729-1747.
259) Fujino T, Goyama S, Sugiura Y, Inoue D, Asada S, Yamasaki S, Matsumoto A, Yamaguchi K, Isobe Y, Tsuchya A, Shikata S, et al. Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway. Nature Commun 2021; 12: 1826.
260) Dawoud A, Tapper WJ, Cross N. Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 2020; 34(10): 2660-2672.