MOLECULAR HETEROGENEITY IN ACUTE PROMYELOCYTIC LEUKEMIA - A SINGLE CENTRE EXPERIENCE FROM INDIA

Nikhil Rabade, Goutham Raval, Shruti Chaudhary, PG Subramanian, Rohan Kodgule, Swapnali Joshi, Prashant Tembhare, Hasmukh Jain, Manju Sengar, Syed Hasan K, Pratibha Amare Kadam, Dhanalaxmi Shetty, Gaurav Narula, Shripad Banavali, Sumeet Gujral, Nikhil Patkar
  • Nikhil Rabade
    Tata Memorial Centre, Mumbai,
  • Goutham Raval
    Tata Memorial Centre, Mumbai,
  • Shruti Chaudhary
    Tata Memorial Centre, Mumbai,
  • PG Subramanian
    Tata Memorial Centre, Mumbai,
  • Rohan Kodgule
    Tata Memorial Centre, Mumbai,
  • Swapnali Joshi
    Tata Memorial Centre, Mumbai,
  • Prashant Tembhare
    Tata Memorial Centre, Mumbai,
  • Hasmukh Jain
    Tata Memorial Centre, Mumbai,
  • Manju Sengar
    Tata Memorial Centre, Mumbai,
  • Syed Hasan K
    Tata Memorial Centre, Mumbai,
  • Pratibha Amare Kadam
    Tata Memorial Centre, Mumbai,
  • Dhanalaxmi Shetty
    Tata Memorial Centre, Mumbai,
  • Gaurav Narula
    Tata Memorial Centre, Mumbai,
  • Shripad Banavali
    Affiliation not present
  • Sumeet Gujral
    Tata Memorial Centre, Mumbai,

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

Keywords

Acute promyelocytic leukemia molecular subtypes in India, variant APL, PLZF-RARA, rare translocations of APL

Full Text:

PDF
HTML
Submitted: 2017-08-24 08:39:55
Published: 2018-01-01 00:00:00
Search for citations in Google Scholar
Related articles: Google Scholar

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract views:
1772

Views:
PDF
96
HTML
765

Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM


Copyright (c) 2017 Mediterranean Journal of Hematology and Infectious Diseases

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
 
© PAGEPress 2008-2018     -     PAGEPress is a registered trademark property of PAGEPress srl, Italy.     -     VAT: IT02125780185     •     Privacy