MOLECULAR HETEROGENEITY IN ACUTE PROMYELOCYTIC LEUKEMIA - A SINGLE CENTRE EXPERIENCE FROM INDIA
Main Article Content
Keywords
Acute promyelocytic leukemia molecular subtypes in India, variant APL, PLZF-RARA, rare translocations of APL
Abstract
Atypical breakpoints and variant APL cases involving alternative chromosomal aberrations are seen in a small subset of acute promyelocytic leukemia (APL) patients. Over 7 different partner genes for RARA have been described. Although rare, these variants prove to be a diagnostic challenge and require combination of advanced cytogenetic and molecular techniques for accurate characterization. Heterogeneity occurs not only at the molecular level but also at clinico-pathological level influencing treatment response and outcome. In this case series we describe the molecular heterogeneity of APL seen in a single tertiary referral centre with a focus on seven variant APL cases from a single tertiary cancer center in India over a period of two and a half years. We discuss five cases with PLZF-RARA fusion and two novel PML-RARA variants, including a Bcr3 variant involving fusion of PML exon4 and RARA exon3 with an additional 40 nucleotides originating from RARA intron2, another involving exon 6 of PML and exon 3 of RARA with addition of 126 nucleotides, which mapped to the central portion of RARA intron 2 To the best of our knowledge this is the first of kind case series from India
Downloads
Download data is not yet available.
Abstract 3152
PDF Downloads 844
HTML Downloads 958
References
1. Grimwade D. The pathogenesis of acute promyelocytic leukemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J Haematol. 1999;106(3):591-613. https://doi.org/10.1046/j.1365-2141.1999.01501.x PMid:10468848
2. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia. 2002;16(10):1959-73. https://doi.org/10.1038/sj.leu.2402721
PMid:12357347
3. Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Francais de Cytogenetique Hematologique, Groupe de Francais d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Blood. 2000;96(4):1297-308. PMid:10942371
4. Adams J, Nassiri M. Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations. Arch Pathol Lab Med. 2015;139(10):1308-13. https://doi.org/10.5858/arpa.2013-0345-RS PMid:26414475
5. Grimwade D, Mistry AR, Solomon E, Guidez F. Acute promyelocytic leukemia: a paradigm for differentiation therapy. Cancer Treat Res. 2010;145:219-35. https://doi.org/10.1007/978-0-387-69259-3_13 PMid:20306254
6. Jovanovic JV, Rennie K, Culligan D, Peniket A, Lennard A, Harrison J, et al. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute promyelocytic leukemia. Front Oncol. 2011;1:35.
https://doi.org/10.3389/fonc.2011.00035
PMid:22655241 PMCid:PMC3356041
7. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.
https://doi.org/10.1006/meth.2001.1262 PMid:11846609
8. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13(12):1901-28.
https://doi.org/10.1038/sj.leu.2401592 PMid:10602411
9. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program. Leukemia. 2003;17(12):2318-57. https://doi.org/10.1038/sj.leu.2403135 PMid:14562125
10. Hasan SK, Mays AN, Ottone T, Ledda A, La Nasa G, Cattaneo C, et al. Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood. 2008;112(8):3383-90. https://doi.org/10.1182/blood-2007-10-115600 PMid:18650449 PMCid:PMC2954750
11. Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96(4):1247-53. PMid:10942364
12. Sainty D, Liso V, Cantu-Rajnoldi A, Head D, Mozziconacci MJ, Arnoulet C, et al. A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Blood. 2000;96(4):1287-96. PMid:10942370
13. Ossenkoppele GJ, van de Loosdrecht AA, Schuurhuis GJ. Review of the relevance of aberrant antigen expression by flow cytometry in myeloid neoplasms. Br J Haematol. 2011;153(4):421-36. https://doi.org/10.1111/j.1365-2141.2011.08595.x PMid:21385170
14. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, etal. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-66. https://doi.org/10.1056/NEJMoa041974 PMid:15659725
15. Chatterjee T, Gupta S, Sharma S, Ganguli P. Distribution of Different PML/RARalpha bcr Isoforms in Indian Acute Promyelocytic Leukemia (APL) Patients and Clinicohematological Correlation. Mediterr J Hematol Infect Dis. 2014;6(1):e2014004.
https://doi.org/10.4084/mjhid.2014.004
PMid:24455113 PMCid:PMC3894845
16. Sazawal S, Hasan SK, Dutta P, Kumar B, Kumar R, Kumar L, et al. Over-representation of bcr3 subtype of PML/RARalpha fusion gene in APL in Indian patients. Ann Hematol. 2005;84(12):781-4. https://doi.org/10.1007/s00277-005-1095-4 PMid:16132910
17. Dutta P, Sazawal S, Kumar R, Saxena R. Does acute promyelocytic leukemia in Indian patients have biology different from the West? Indian J Pathol Microbiol. 2008;51(3):437-9.
https://doi.org/10.4103/0377-4929.42555 PMid:18723985
18. Slack JL, Willman CL, Andersen JW, Li YP, Viswanatha DS, Bloomfield CD, et al. Molecular analysis and clinical outcome of adult APL patients with the type V PML-RARalpha isoform: results from intergroup protocol 0129. Blood. 2000;95(2):398-403. PMid:10627441
19. Reiter A, Saussele S, Grimwade D, Wiemels JL, Segal MR, Lafage-Pochitaloff M, et al. Genomic anatomy of the specific reciprocal
translocation t(15;17) in acute promyelocytic leukemia. Genes Chromosomes Cancer. 2003;36(2):175-88.
https://doi.org/10.1002/gcc.10154 PMid:12508246
20. Jeziskova I, Razga F, Gazdova J, Doubek M, Jurcek T, Koristek Z, et al. A case of a novel PML/RARA short fusion transcript with truncated transcription variant 2 of the RARA gene. Mol Diagn Ther. 2010;14(2):113-7. https://doi.org/10.1007/BF03256361
PMid:20359255
21. Spicuglia S, Vincent-Fabert C, Benoukraf T, Tiberi G, Saurin AJ, Zacarias-Cabeza J, et al. Characterisation of genome-wide PLZF/RARA target genes. PLoS One. 2011;6(9):e24176. https://doi.org/10.1371/journal.pone.0024176 PMid:21949697
PMCid:PMC3176768
22. George B, Poonkuzhali B, Srivastava VM, Chandy M, Srivastava A. Hematological and molecular remission with combination chemotherapy in a patient with PLZF-RARalpha acute promyelocytic leukemia (APML). Ann Hematol. 2005;84(6):406-8.
https://doi.org/10.1007/s00277-004-0979-z PMid:15592671
23. Rohr SS, Pelloso LA, Borgo A, De Nadai LC, Yamamoto M, Rego EM, et al. Acute promyelocytic leukemia associated with the PLZF-RARA fusion gene: two additional cases with clinical and laboratorial peculiar presentations. Med Oncol. 2012;29(4):2345-7.
https://doi.org/10.1007/s12032-011-0147-y PMid:22205181
2. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia. 2002;16(10):1959-73. https://doi.org/10.1038/sj.leu.2402721
PMid:12357347
3. Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Francais de Cytogenetique Hematologique, Groupe de Francais d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Blood. 2000;96(4):1297-308. PMid:10942371
4. Adams J, Nassiri M. Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations. Arch Pathol Lab Med. 2015;139(10):1308-13. https://doi.org/10.5858/arpa.2013-0345-RS PMid:26414475
5. Grimwade D, Mistry AR, Solomon E, Guidez F. Acute promyelocytic leukemia: a paradigm for differentiation therapy. Cancer Treat Res. 2010;145:219-35. https://doi.org/10.1007/978-0-387-69259-3_13 PMid:20306254
6. Jovanovic JV, Rennie K, Culligan D, Peniket A, Lennard A, Harrison J, et al. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute promyelocytic leukemia. Front Oncol. 2011;1:35.
https://doi.org/10.3389/fonc.2011.00035
PMid:22655241 PMCid:PMC3356041
7. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.
https://doi.org/10.1006/meth.2001.1262 PMid:11846609
8. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13(12):1901-28.
https://doi.org/10.1038/sj.leu.2401592 PMid:10602411
9. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program. Leukemia. 2003;17(12):2318-57. https://doi.org/10.1038/sj.leu.2403135 PMid:14562125
10. Hasan SK, Mays AN, Ottone T, Ledda A, La Nasa G, Cattaneo C, et al. Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood. 2008;112(8):3383-90. https://doi.org/10.1182/blood-2007-10-115600 PMid:18650449 PMCid:PMC2954750
11. Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96(4):1247-53. PMid:10942364
12. Sainty D, Liso V, Cantu-Rajnoldi A, Head D, Mozziconacci MJ, Arnoulet C, et al. A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Blood. 2000;96(4):1287-96. PMid:10942370
13. Ossenkoppele GJ, van de Loosdrecht AA, Schuurhuis GJ. Review of the relevance of aberrant antigen expression by flow cytometry in myeloid neoplasms. Br J Haematol. 2011;153(4):421-36. https://doi.org/10.1111/j.1365-2141.2011.08595.x PMid:21385170
14. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, etal. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-66. https://doi.org/10.1056/NEJMoa041974 PMid:15659725
15. Chatterjee T, Gupta S, Sharma S, Ganguli P. Distribution of Different PML/RARalpha bcr Isoforms in Indian Acute Promyelocytic Leukemia (APL) Patients and Clinicohematological Correlation. Mediterr J Hematol Infect Dis. 2014;6(1):e2014004.
https://doi.org/10.4084/mjhid.2014.004
PMid:24455113 PMCid:PMC3894845
16. Sazawal S, Hasan SK, Dutta P, Kumar B, Kumar R, Kumar L, et al. Over-representation of bcr3 subtype of PML/RARalpha fusion gene in APL in Indian patients. Ann Hematol. 2005;84(12):781-4. https://doi.org/10.1007/s00277-005-1095-4 PMid:16132910
17. Dutta P, Sazawal S, Kumar R, Saxena R. Does acute promyelocytic leukemia in Indian patients have biology different from the West? Indian J Pathol Microbiol. 2008;51(3):437-9.
https://doi.org/10.4103/0377-4929.42555 PMid:18723985
18. Slack JL, Willman CL, Andersen JW, Li YP, Viswanatha DS, Bloomfield CD, et al. Molecular analysis and clinical outcome of adult APL patients with the type V PML-RARalpha isoform: results from intergroup protocol 0129. Blood. 2000;95(2):398-403. PMid:10627441
19. Reiter A, Saussele S, Grimwade D, Wiemels JL, Segal MR, Lafage-Pochitaloff M, et al. Genomic anatomy of the specific reciprocal
translocation t(15;17) in acute promyelocytic leukemia. Genes Chromosomes Cancer. 2003;36(2):175-88.
https://doi.org/10.1002/gcc.10154 PMid:12508246
20. Jeziskova I, Razga F, Gazdova J, Doubek M, Jurcek T, Koristek Z, et al. A case of a novel PML/RARA short fusion transcript with truncated transcription variant 2 of the RARA gene. Mol Diagn Ther. 2010;14(2):113-7. https://doi.org/10.1007/BF03256361
PMid:20359255
21. Spicuglia S, Vincent-Fabert C, Benoukraf T, Tiberi G, Saurin AJ, Zacarias-Cabeza J, et al. Characterisation of genome-wide PLZF/RARA target genes. PLoS One. 2011;6(9):e24176. https://doi.org/10.1371/journal.pone.0024176 PMid:21949697
PMCid:PMC3176768
22. George B, Poonkuzhali B, Srivastava VM, Chandy M, Srivastava A. Hematological and molecular remission with combination chemotherapy in a patient with PLZF-RARalpha acute promyelocytic leukemia (APML). Ann Hematol. 2005;84(6):406-8.
https://doi.org/10.1007/s00277-004-0979-z PMid:15592671
23. Rohr SS, Pelloso LA, Borgo A, De Nadai LC, Yamamoto M, Rego EM, et al. Acute promyelocytic leukemia associated with the PLZF-RARA fusion gene: two additional cases with clinical and laboratorial peculiar presentations. Med Oncol. 2012;29(4):2345-7.
https://doi.org/10.1007/s12032-011-0147-y PMid:22205181