Eleftheria Lamprianidou1, Chryssoula Kordella1, Menelaos Papoutselis1, Zoi Bezyrgiannidou1, Evangelia Nakou1, Spyros Papamichos1, Emmanouil Spanoudakis1, Andreas Giannopoulos2, Katerina Zoi2 and Ioannis Kotsianidis1.
1 Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece.
2 Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Received: August 31, 2017
Accepted: October 12, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017066 DOI 10.4084/MJHID.2017.066
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neoplasms with isolated isochromosome 17q [MN i(17q)] has been
described as a distinct entity with poor prognosis. However, literature
reports show a considerable clinical and molecular heterogeneity. We
describe a 58-year-old male patient who was diagnosed as refractory
anemia with multilineage dysplasia and ringed sideroblasts with
isolated i(17q). Though he initially responded well to erythropoietin,
he gradually progressed to an aggressive form of MDS/MPN refractory to
azacytidine and died 29 months after the first diagnosis. Notably, in
contrast to disease advancement, his karyotype reverted to normal,
whereas his mutational profile remained unchanged. To our knowledge,
this is the first report of karyotype normalization during disease
progression in patients with MN i(17q). It suggests that the i(17q)
anomaly is dispensable for the leukemic transformation and highlighting
the underlying clinical and molecular complexity which both has to be
resolved before the establishment of MN with isolated i(17q) as a
In the present manuscript, we describe a 58-year old male patient with isolated i(17q) who initially presented at our department as refractory anemia with multilineage dysplasia with ringed sideroblasts (RCMD-RS). Two years later he progressed to a fibrotic MDS/MPN with excess blasts, while, at the same time, his karyotype converted to normal. Our case supports the existence of recurrent characteristic features in MDS with isolated i(17q) but argues on the effect on survival and the causality of isolated i(17q) anomaly in leukemic progression.
|Table 1. Clinical and biological characteristics of MDS patients with i(17q) in studies including ≥ 10 patients.|
By contrast, in line with the 29-month survival of our patient, two other large series recorded an mOS of 30 and 26.5 months. The exclusion of AML patients from the latter studies may account for the discrepant findings; indeed, MDS patients with isolated i(17q) are assigned to the intermediate-risk category by the revised international prognostic scoring system (IPSS-R) and have a predicted mOS of 32 months. Of note, MDS/MPN patients fared worse than the AML ones in one study, but 4 out of 14 MDS/MPN cases were actually secondary AML.
As concerns treatment, myeloid neoplasms with isolated i(17q) are apparently resistant to standard regimens, and such patients are candidates for allogeneic transplantation early in the course of the disease.[5,10] Data regarding the efficacy of hypomethylating agents in these patients are very limited; Kanagal-Shamanna et al. reported on 5 patients, three in azacytidine and two in decitabine, all of which failed to respond, similarly to our patient.
The more obvious consequence of the formation of isochromosome 17q is the deletion of one allele of TP53 gene located at 17p13. Loss of 17p might be responsible for the Pelger-Huët dysgranulopoiesis, but coding mutations in the remaining allele are rare and usually accompanied by additional cytogenetic abnormalities, rendering TP53 an improbable player in the pathobiology of the syndrome.[2,3]
ASXL1, SRSF2, RAS, and SETBP1 are the most frequently mutated genes in isolated i(17q) (Table 2). The former three mutations may antedate the formation of i(17q), whereas SETBP1 mutations are associated with i(17q). Our patient had mutations in SETBP1, U2AF1, and c-KIT, whereas ASXL1 was unmutated and no mutation analysis was performed in SRSF2 and RAS. Mutations in SETBP1, mainly gain of function, are often observed in CMML, secondary AML and atypical CML, while they are rare in childhood, de novo and therapy-related AML.[14,15] Though linked with characteristics of poor prognosis, reports on the effect of SETBP1 mutations on survival are conflicting.[14,15] Our patient also had the U2AF1 (p.Q157P) mutation, rarely reported in MDS with isolated i(17q), while it is more common in poor prognosis, advanced myelomonocytic leukemias. U2AF1 mutations appear to lead to pathological splicing of several genes involved in leukemogenesis and are strongly associated with leukemic evolution and dismal outcome. We also detected the KIT (p.D816V) mutation, which is observed in over 90% of systemic mastocytosis cases and at lower frequencies in patients with core binding factor AML conferring a poor prognosis. Activating mutations of KIT in AML are considered as a class I aberrations which provide a proliferative and survival advantage to the leukemic cells. In MDS the above mutation is rarely found and is restricted to advanced stages, whereas only one case of a different KIT mutation has been reported so far as a sole molecular aberration in a patient with AML with myelodysplasia-related changes and isolated i(17q). Interestingly, both U2AF1 and KIT mutations antedated leukemic progression by two years in our patient, emphasizing the often existing discordance between mutational profiles and clinical course and the need for caution in the clinical translation of molecular findings. In addition, the intriguing conversion of our patient’s karyotype to normal during disease progression suggests that genetic pathways unrelated to chromosome 17 are potentially involved in the multifactorial pathobiology of this MDS entity. A hint of the dispensability of i(17q) for the leukemic progression has been previously reported in one patient with primary myelofibrosis who developed a transient and progressively shrinking i(17q) clone without changing his mutational profile. Another indication that the development of i(17q) anomaly may represent an epiphenomenon and not the initial oncogenic event is the fact that though the mutational profile of our patient remained unchanged, the mutational load of each mutated gene increased significantly during disease progression (data not shown). Thus, the leukemogenic effect of one or more of SETBP1, U2AF1 and KIT mutants appears to be independent of the i(17)q formation. Nevertheless, the similarity in the clinical presentation of cases with isolated i(17)q still suggests a role of this abnormality in the characteristic features shared by these patients.
|Table 2. Most frequently mutated genes in isolated i(17q).|
- Mertens F, Johansson B, Mitelman F. Isochromosomes in neoplasia. Genes Chromosomes Cancer. 1994;10(4):221-30. https://doi.org/10.1002/gcc.2870100402 PMid:7522535
- Fioretos T, Strombeck B, Sandberg T, Johansson B, Billstrom R, Borg A, et al. Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations. Blood. 1999;94(1):225-32. PMid:10381517
- Kanagal-Shamanna R, Luthra R, Yin CC, Patel KP, Takahashi K, Lu X, et al. Myeloid neoplasms with isolated isochromosome 17q demonstrate a high frequency of mutations in SETBP1, SRSF2, ASXL1 and NRAS. Oncotarget. 2016;7(12):14251-8. https://doi.org/10.18632/oncotarget.7350 PMid:26883102 PMCid:PMC4924712
- Mitelman F, Brandt L, Nilsson PG. Relation among occupational exposure to potential mutagenic/carcinogenic agents, clinical findings, and bone marrow chromosomes in acute nonlymphocytic leukemia. Blood. 1978;52(6):1229-37. PMid:719175
- Kanagal-Shamanna R, Bueso-Ramos CE, Barkoh B, Lu G, Wang S, Garcia-Manero G, et al. Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53. Cancer. 2012;118(11):2879-88. https://doi.org/10.1002/cncr.26537 PMid:22038701
- Visconte V, Tabarroki A, Zhang L, Hasrouni E, Gerace C, Frum R, et al. Clinicopathologic and molecular characterization of myeloid neoplasms harboring isochromosome 17(q10). American journal of hematology. 2014;89(8):862. https://doi.org/10.1002/ajh.23755 PMid:24796269
- McClure RF, Dewald GW, Hoyer JD, Hanson CA. Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course. British journal of haematology. 1999;106(2):445-54. https://doi.org/10.1046/j.1365-2141.1999.01537.x PMid:10460605
- Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-51. https://doi.org/10.1182/blood-2009-03-209262 PMid:19357394
- Lazarevic V, Djordjevic V, Magic Z, Marisavljevic D, Colovic M. Refractory anemia with ring sideroblasts associated with i(17q) and mutation of the TP53 gene. Cancer Genet Cytogenet. 2002;136(1):86-9. https://doi.org/10.1016/S0165-4608(02)00510-1
- Becher R, Carbonell F, Bartram CR. Isochromosome 17q in Ph1-negative leukemia: a clinical, cytogenetic, and molecular study. Blood. 1990;75(8):1679-83. PMid:2328318
- Adema V, Larrayoz MJ, Calasanz MJ, Palomo L, Patino-Garcia A, Agirre X, et al. Correlation of myelodysplastic syndromes with i(17)(q10) and TP53 and SETBP1 mutations. British journal of haematology. 2015;171(1):137-41. https://doi.org/10.1111/bjh.13355 PMid:25716545
- Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-65. https://doi.org/10.1182/blood-2012-03-420489 PMid:22740453 PMCid:PMC4425443
- Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M, Lepelley P, et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia. 1995;9(3):370-81. PMid:7885035
- Damm F, Itzykson R, Kosmider O, Droin N, Renneville A, Chesnais V, et al. SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias. Leukemia. 2013;27(6):1401-3. https://doi.org/10.1038/leu.2013.35 PMid:23443343
- Meggendorfer M, Haferlach C, Zenger M, Macijewski K, Kern W, Haferlach T. The landscape of myeloid neoplasms with isochromosome 17q discloses a specific mutation profile and is characterized by an accumulation of prognostically adverse molecular markers. Leukemia. 2016;30(7):1624-7. https://doi.org/10.1038/leu.2016.21 PMid:26859077
- Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S, Jerez A, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood. 2012;119(14):3203-10. https://doi.org/10.1182/blood-2011-12-399774 PMid:22323480 PMCid:PMC3321850
- Przychodzen B, Jerez A, Guinta K, Sekeres MA, Padgett R, Maciejewski JP, et al. Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood. 2013;122(6):999-1006. https://doi.org/10.1182/blood-2013-01-480970 PMid:23775717 PMCid:PMC3739042
- Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107(5):1791-9. https://doi.org/10.1182/blood-2005-04-1466 PMid:16254134
- Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. The New England journal of medicine. 2008;358(18):1909-18. https://doi.org/10.1056/NEJMoa074306 PMid:18450602
- Bacher U, Haferlach T, Kern W, Haferlach C, Schnittger S. A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia. Haematologica. 2007;92(6):744-52. https://doi.org/10.3324/haematol.10869 PMid:17550846
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