Frequency of FLT3 (ITD, D835) Gene Mutations in Acute Myelogenous Leukemia: a Report from Northeastern Iran

  • Allahyari, Abolghasem (Department of Hematology-Oncology, Emam Reza Hospital, School of Medicine, Mashhad University of Medical Sciences) ;
  • Sadeghi, Masoud (Medical Biology Research Center, Kermanshah University of Medical Sciences) ;
  • Ayatollahi, Hossein (Department of Hematology and Blood Banking, Cancer Molecular Pathology Research Center, Ghaem Hospital, Mashhad University of Medical Sciences) ;
  • Yazdi, Hamed Najjaran (Department of Internal Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences) ;
  • Tavakol, Mohammad (Department of Internal Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences)
  • Published : 2016.09.01

Abstract

Background: FLT3 is mutated in about 1/3 of acute myelogenous leukemia (AML) patients. The aim of the present study was to report the prevalence of FLT3 mutations and comparison with prognostic factors in AML patients in the Northeastern of Iran. Materials and Methods: This cross-sectional study concerned 100 AML cases diagnosed based on bone marrow aspiration and peripheral blood. DNA for every AML patient was extracted and underwent PCR with FLT3-ITD primers. Results: The mean age at diagnosis was 28.5 years (range, 1-66 years), 52 patients (52%) being male. Out of 100 AML patients, 21 (21%) had FLT3 mutation, (17 with FLT3-ITD, 81%, and 4 with FLT3-D825, 19%). Of the 21, 14 (66.7%) had heterozygous mutation. There was no significant difference between age, sex and organomegaly between patients with FLT3 mutation versus FLT3 wild-type. Conclusions: Our frequency of FLT3 is in line with earlier fidnings of approximately 20 to 30% and also the prevalence of FLT3-ITD is more than FLT3-D35 mutation. There was no significant difference between prognostic factors (age and sex) in the patients with FLT3 mutation versus FLT3 wild-type. The prevalence of FLT3 heterozygous mutations is more that homozygous mutations in AML patients.

Keywords

References

  1. Alvarado Y, Kantarjian HM, Luthra R, et al (2014). Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. Cancer, 120, 2142-9. https://doi.org/10.1002/cncr.28705
  2. Auewarakul CU, Sritana N, Limwongse C, Thongnoppakhun W, Yenchitsomanus PT (2005). 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, 162, 127-34. https://doi.org/10.1016/j.cancergencyto.2005.03.011
  3. Chillon MC, Fernandez C, Garcia-Sanz R, et al (2004). FLT3- activating mutations are associated with poor prognostic features in AML at diagnosis but they are not an independent prognostic factor. Hematol J, 5, 239-46. https://doi.org/10.1038/sj.thj.6200382
  4. Dehbi H, Kassogue Y, Nasserddine S, Quessar A, Nadifi S (2013). FLT3-ITD incidence and FLT-D835 mutations in acute myeloid leukemia patients with normal karyotype in Morocco, a preliminary study. Middle East J Cancer, 4, 1-5
  5. Dicker F, Haferlach C, Sundermann J, et al (2010) Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML. Leukemia, 24, 1528-32. https://doi.org/10.1038/leu.2010.124
  6. Elyamany G, Awad M, Fadalla K, et al (2014). Frequency and prognostic relevance of FLT3 mutations in saudi acute myeloid leukemia patients. Adv Hematol, 2014, 141360.
  7. Gari M, Abuzenadah A, Chaudhary A, et al (2008). Detection of FLT3 oncogene mutations in acute myeloid leukemia using conformationsensitive gel electrophoresis. Int J Mol Sci, 9, 2194-204. https://doi.org/10.3390/ijms9112194
  8. Gilliland DG, Griffin JD (2002). The roles of FLT3 in hematopoiesis and leukemia. Blood, 100, 1532-42. https://doi.org/10.1182/blood-2002-02-0492
  9. Green C, Linch DC, Gale RE (2008) Most acute myeloid leukaemia patients with intermediate mutant FLT3/ITD levels do not have detectable bi-allelic disease, indicating that heterozygous disease alone is associated with an adverse outcome. Br J Haematol, 142, 423-6. https://doi.org/10.1111/j.1365-2141.2008.07196.x
  10. Kiyoi H, Naoe T (2006). FLT3 mutations in acute myeloid leukemia. Methods Mol Med, 125, 189-97.
  11. Kok CH, Brown AL, Perugini M, et al (2013) The preferential occurrence of FLT3-TKD mutations in inv(16) AML and impact on survival outcome, a combined analysis of 1053 core-binding factor AML patients. Br J Haematol, 160, 557-9. https://doi.org/10.1111/bjh.12131
  12. Kooshyar MM, Sadeghian MH, Keramati MR, et al (2015). Frequency of FLT3 ITD and FLT3 TKD Mutations in Multiple Myeloma Patients (A Case Control Study). Inter Jour Med Lab, 2, 34-40.
  13. Lee BH, Tothova Z, Levine RL, et al (2007). FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell, 12, 367-80. https://doi.org/10.1016/j.ccr.2007.08.031
  14. Levis M, Small D (2010). FLT3, ITDoes matter in leukemia. Leukemia, 17, 1738-52.
  15. McCormick SR, McCormick MJ, Grutkoski PS, et al (2010). FLT3 mutations at diagnosis and relapse in acute myeloid leukemia, cytogenetic and pathologic correlations, including cuplike blast morphology. Arch Pathol Lab Med, 134, 1143-51.
  16. Mead AJ, Linch DC, Hills RK, et al (2007) FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood, 110, 1262-70. https://doi.org/10.1182/blood-2006-04-015826
  17. Payandeh M, Khodarahmi R, Sadeghi M, Sadeghi E (2015). Appearance of acute myelogenous leukemia (AML) in a patient with breast cancer after adjuvant chemotherapy, case report and review of the literature. Iran J Cancer Prev, 8, 125-8.
  18. Ruan M, Wang YQ, Zhang L, et al (2011). FLT3 mutations in children with acute myeloid leukemia, a single center study. Zhongguo Dang Dai Er Ke Za Zhi, 13, 863-6 [in Chinese].
  19. Sarojam S, Vijay S, Raveendran S, et al(2014). FLT3 mutation as a significant prognostic marker in de novo acute myeloid leukemia patients, incidence, distribution and association with cytogenetic findings in a study from South India. Middle East J Cancer, 5, 185-96.
  20. Scholl S, Theuer C, Scheble V, et al (2008). Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplications in patients older than 60 yr with acute myeloid leukaemia. Eur J Haematol, 80, 208-15. https://doi.org/10.1111/j.1600-0609.2007.01019.x
  21. Small D (2006). FLT3 mutations, biology and treatment. Hematol Am Soc Hematol Educ Program, 178-84.
  22. Quentmeier H, Reinhardt J, Zaborski M, Drexler HG (2003). FLT3 mutations in acute myeloid leukemia cell lines. Leukemia, 17, 120-4. https://doi.org/10.1038/sj.leu.2402740
  23. Stirewalt DL, Radich JP (2003). The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer, 3, 650-65. https://doi.org/10.1038/nrc1169
  24. Yamamoto Y, Kiyoi H, Nakano Y, et al (2001). Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood, 97, 2434-9. https://doi.org/10.1182/blood.V97.8.2434