Clinical profile of FTL3-ITD mutation in West Algerian population with acute myeloid leukemia

Document Type : Original article

Authors

1 Department of biology, Faculty of Science and Technology, University of Ain Temouchent-Belhadj Bouchaib-, Algeria

2 Service de Cytogénétique et de Biologie moléculaire de l’Etablissement Hospitalo-universitaire d’Oran (1er Novembre)

3 École Supérieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim Mohamed 31003, Oran, Algeria

4 Université des sciences et de la technologie d’Oran Mohamed Boudiaf

5 Service d’hématologie et de thérapie cellulaire de l’Etablissement Hospitalo-universitaire d’Oran (1er Novembre)

6 Département de pharmacie, Faculté de Médecine, Université Oran1

Abstract

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the abnormal and rapid growth of cells. The mutation of the Fms-like tyrosine kinase 3 ligand gene (FLT3-ITD) represents an important factor in the prognosis of AML. The objective of this study was to determine for the first time the prevalence of FLT3-ITD mutation in west Algerian AML patients. A total of 160 AML patients were genotyped for FLT3-ITD mutation by using polymerase chain reaction. FLT3-ITD mutation was detected in 13% of patients. Mutation rates show no significant difference in the distribution of sex and age. A positive association was found between this mutation and a higher leukocyte and blast cells counts. We also found that the M3 and M5 subtype were the commonest in the FLT3 mutated group. This preliminary study provides first-time prevalence estimates for FLT3-ITD mutation in acute myeloid leukemia patients from the West region of Algeria. 

Keywords

References

  1. Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM. Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Rev 2019;36:70-87.
  2. Fernández de Larrea C, Kyle RA, Durie BG, Ludwig H, Usmani S, Vesole DH, Hajek R, San Miguel JF, Sezer O, Sonneveld P, Kumar SK, Mahindra A, Comenzo R, Palumbo A, Mazumber A, Anderson KC, Richardson PG, Badros AZ, Caers J, Cavo M, LeLeu X, Dimopoulos MA, Chim CS, Schots R, Noeul A, Fantl D, Mellqvist U-H, Landgren O, Chanan-Khan A, Moreau P, Fonseca R, Merlini G, Lahuerta JJ, Blade J, Orlowski RZ, Shah JJ, International Myeloma Working Group. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia 2013;27:780-791.
  3. Mandal R, Bolt DM, Shah BK. Disparities in chronic myeloid leukemia survival by age, gender, and ethnicity in pre- and post-imatinib eras in the US. Acta Oncol 2013;52:837-841.
  4. Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 1991;6:1641-1650.
  5. Rosnet O, Schiff C, Pébusque MJ, Marchetto S, Tonnelle C, Toiron Y, Birg F, Birnbaum D. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood 1993;82:1110-1119.
  6. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 1994;368: 643-648.
  7. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100:1532-1542.
  8. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996;10:1911-1918.
  9. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 1998;12:1333-1337.
  10. Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F, Lippke J, Saxena K. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 2004; 13:169-178.
  11. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, Sonoda Y, Abe T, Kahsima K, Matsuo Y, Naoe T. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 1997;11:1605-1609.
  12. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 2005;19:1345-1349.
  13. Marshall RC, Tlagadi A, Bronze M, Kana V, Naidoo S, Wiggill TM, Carmona SC. Lower frequency of NPM1 and FLT3-ITD mutations in a South African adult de novo AML cohort. Int J Lab Hematol 2014;36:656-664.
  14. Kloppers JF, De Kock A, Cronjé J, van Marle AC. Molecular characterisation of NPM1 and FLT3-ITD mutations in a central South African adult de novo acute myeloid leukaemia cohort. Afr J Lab Med 2021;10:1363.
  15. El Gammal MM, Ebid GT, Madney YM, Abo-Elazm OM, Kelany AK, Torra OS, Radich JP. Clinical effect of combined mutations in DNMT3A, FLT3-ITD, and NPM1 among Egyptian acute myeloid leukemia patients. Clin Lymphoma Myeloma Leuk 2019;19: e281-e290.
  16. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, Wermke M, Bornhauser M, Ritter M, Neubauer A, Ehninger G, Illmer T. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002;99:4326-4335.
  17. Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K, AML Study Group Ulm, Acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002;100:4372-4380.
  18. Auewarakul CU, Sritana N, Limwongse C, Thongnoppakhun W, Yenchitsomanus PT. Mutations of the FLT3 gene in adult acute myeloid leukemia: determination of incidence and identification of a novel mutation in a Thai population. Cancer Genet Cytogenet 2005; 162:127-134.
  19. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001;98:1752-1759.
  20. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohn P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005;105:54-60.
  21. Borthakur G, Kantarjian H, Patel KP, Ravandi F, Qiao W, Faderl S, Kadia T, Luthra R, Pierce S, Cortes JE. Impact of numerical variation in FMS-like tyrosine kinase receptor 3 internal tandem duplications on clinical outcome in normal karyotype acute myelogenous leukemia. Cancer 2012;118:5819-5822.
  22. Grimwade D. The changing paradigm of prognostic factors in acute myeloid leukaemia. Best Pract Res Clin Haematol 2012;25:419-425.
  23. Wahlin A, Hörnsten P, Jonsson H. Remission rate and survival in acute myeloid leukemia: Impact of selection and chemotherapy. Eur J Haematol 1991;46:240-247.
  24. Phekoo KJ, Richards MA, Møller H, Schey SA, South Thames Haematology Specialist Committee. The incidence and outcome of myeloid malignancies in 2,112 adult patients in southeast England. Haematologica 2006;91:1400-1404.
  25. Deeg HJ. Not all patients with AML over 60 years of age should be offered early allogeneic stem cell transplantation. Blood Adv 2022;6:1623-1627.
  26. Sultan S, Zaheer HA, Irfan SM, Ashar S. Demographic and clinical characteristics of adult acute myeloid leukemia--tertiary care experience. Asian Pac J Cancer Prev 2016;17:357-360.
  27. Ayachi OS, Rezgoun ML, Sayitoglu M, Altindirek D, Erbilgin Y, Abadi N, Satta D. Prevalence and effect evaluation of FLT3 and NPM1 mutations in acute myeloid leukemia patients in Eastern Algeria. Inter J Hemat Oncol 2018;28:169-179.
  28. Miller BA, Chu KC, Hankey BF, Ries LA. Cancer incidence and mortality patterns among specific Asian and Pacific Islander populations in the U.S. cancer causes control 2008; 19:227-256.
  29. Ali A, Siddique MK, Gale RE, Shakoori AR. Frequency of FLT3/ITD Mutations in Pakistani acute myeloid leukemia patients. Pakistan J Zool 2013;45:495-501.
  30. Elyamany G, Awad M, Fadalla K, Albalawi M, Al Shahrani M, Al Abdulaaly A. Frequency and prognostic relevance of FLT3 mutations in Saudi acute myeloid leukemia patients. Adv Hematol 2014;2014:141360.
  31. Aly R, Shahin D, Azmy E. Prognostic significance of FLT3 internal tandem duplication in Egyptian acute myeloid leukemia and normal cytogenetics. Comp Clin Pathol 2012;21: 1029-1035.
  32. Mat Yusoff Y, Abu Seman Z, Othman N, Kamaluddin NR, Esa E, Zulkiply NA, Abdullah J, Zakaria Z. Identification of FLT3 and NPM1 mutations in patients with acute myeloid leukaemia. Asian Pac J Cancer Prev 2019;20:1749-1755.
  33. Ishfaq M, Malik A, Faiz M, Sheikh I, Asif M, Khan MN, Qureshi MS, Zahid S, Manan A, Arooj M, Qazi MH, Chaudhary A, Alqahtani MH, Rasool M. Molecular characterization of FLT3 mutations in acute leukemia patients in Pakistan. Asian Pac J Cancer Prev 2012;13: 4581-4585.
  34. Xu YY, Gao L, Ding Y, Sun JZ, Wang N, Wang LL, Yu L. [Detection and clinical significance of FLT3-ITD gene mutation in patients with acute myeloid leukemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2012;20:1312-1315.
  35. Cuervo-Sierra J, Jaime-Pérez JC, Martínez-Hernández RA, García-Sepúlveda RD, Sánchez-Cárdenas M, Gómez-Almaguer D, Ortíz-López R, Villarreal-Villarreal CD, Ruiz-Arguelles GJ, Ruiz-Delgado G, Lutz-Presno J, Garcés-Eisele J, Ignacio-Ibarra G, Muciño-Hernández G, Arana-Trejo RM, Jiménez-Mejia AM, Vásquez-Palacio G. Prevalence and clinical significance of FLT3 mutation status in acute myeloid leukemia patients: A multicenter study. Arch Med Res 2016;47:172-179.
  36. Allahyari A, Sadeghi M, Ayatollahi H, Yazdi HN, Tavakol M. Frequency of FLT3 (ITD, D835) gene mutations in acute myelogenous leukemia: a report from Northeastern Iran. Asian Pac J Cancer Prev 2016;17:4319-4322.
  37. Notopuro PB, Jusak N, Harianto N. Detection of flt3 gene mutations in patients with acute myeloid leukemia in surabaya, indonesia: A single-center study. Iran J Blood Cancer 2020; 12:54-57.
  38. Kondo M, Horibe K, Takahashi Y, Matsumoto K, Fukuda M, Inaba J, Kato K, Kojima S, Matsuyama T. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol 1999;33:525-529.
  39. Su L, Li W, Cui JW, Tan YH, Yang Y, Liu XL, Yu P, Hu RP, Wang LL, Gao SJ. [Correlation of NPM1, FLT3-ITD mutations with leukocyte count and myeloblasts percentage in AML patients with normal karyotype]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2013;21:571-575.
  40. de Jonge HJ, Valk PJ, de Bont ES, Schuringa JJ, Ossenkoppele G, Vellenga E, Huls G. Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD. Haematologica 2011;96:1310-1317.
  41. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, Loffler H, Sauerland CM, Serve H, Buchner T, Haferlach T, Hiddemann W. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002;100:59-66. 

Files

Share

How to cite

Statistics