Document Type : Original Research


1 Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran

2 Cancer Molecular Pathology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

3 Laboratory science expert, Mashhad university of medical sciences, Mashhad, Iran

4 Departmant of Hemathology, School of Allied Medical Science, Iran University of Medical Science, Tehran,IRAN.

5 Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Mashhad University of Medical Sciences, Mashhad, Iran.

6 Assistant professor of biostatistical sciences ,mashhad university of medical sciences, Mashhad University of Medical Sciences, Mashhad, Iran


Background & Objective: Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by genetic abnormalities. These days, molecular and genetic factors are usually used as diagnostic and prognostic markers. FLT-3 is one of the most known diagnostic factors in AML. MDR1 gene belongs to the ATP binding cassette family; it is known as one of the chemotherapy-resistant causes of AML. We aimed to study FLT-3ITD mutations and their association with MDR1 gene expression in AML individuals.
Methods: For investigation, 80 AML individuals and 20 healthy controls were selected. This study was done in the cancer molecular pathology research center of Mashhad University of Medical Sciences (MUMS), Iran during 2017-2019. FLT3-ITD mutation was assessed by polymerase chain reaction (PCR); Real-time quantitative PCR was performed to measure the amount of MDR1 gene expression. Bone marrow and blood smears of patients were evaluated in terms of morphology. SPSS 16.0 was used for data analysis.
Results: FLT3-ITD mutation and MDR1 overexpression were found in 18.8% and 23.8% of AML patients, respectively. Statistical analysis did not show any relations or association between these two markers. Cuplike morphology was observed in blast cells in 21.25% of AML cases, which was associated with FLT3-ITD mutation presence.
Conclusion: FLT-3 and MDR1 do not affect each other. It is suggested to perform survival studies to determine the exact role of MDR1 overexpression in drug resistance issues.


Main Subjects

  1. Fathi AT, Chen YB. The role of FLT 3 inhibitors in the treatment of FLT 3‐mutated acute myeloid leukemia. Eur J Haematol. 2017;98(4):330-6. [DOI:10.1111/ejh.12841] [PMID]
  2. Kassem NM, Medhat N, Kassem HA, El-Desouky MA. Chemotherapeutic Resistance in Egyptian Acute Myeloid Leukemia Patients. Asian Pac J Cancer Prev. 2019;20(8):2421-7. [DOI:10.31557/APJCP.2019.20.8.2421] [PMID] [PMCID]
  3. Koczkodaj D, Zmorzynski S, Michalak-Wojnowska M, Wasik-Szczepanek E, Filip AA. Examination of the FLT3 and NPM1 mutational status in patients with acute myeloid leukemia from southeastern Poland. Arch Med Sci. 2016;12(1):120-8. [PMID] [PMCID] [DOI:10.5114/aoms.2015.49811]
  4. 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(8):1345-9. [DOI:10.1038/sj.leu.2403838] [PMID]
  5. Sazawal S, Singh N, Jain S, Chhikara S, Chaubey R, Bhattacharyya J, et al. NPM1 and FLT3 mutations in acute myeloid leukemia with normal karyotype: Indian perspective. Indian J Pathol Microbiol. 2017;60(3):355-9. [DOI:10.4103/IJPM.IJPM_501_15] [PMID]
  6. Tiribelli M, Geromin A, Michelutti A, Cavallin M, Pianta A, Fabbro D, et al. Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse. Cancer. 2011;117 (10):2156-62. [DOI:10.1002/cncr.25753] [PMID]
  7. Tian Q, Deng WJ, Li ZW. Identification of a novel crizotinib-sensitive BCL11A-ALK gene fusion in a nonsmall cell lung cancer patient. Eur Respir J. 2017;49(4):1602149. [DOI:10.1183/13993003.02149-2016] [PMID]
  8. Xutao G, PengCheng S, Yin L, Huijuan D, Yan W, Haiqing Z, et al. BCL11A and MDR1 expressions have prognostic impact in patients with acute myeloid leukemia treated with chemotherapy. Pharmacogenomics. 2018;19(4): 343-8. [DOI:10.2217/pgs-2017-0157] [PMID]
  9. Alyaqubi KJ, AL-Faisal AHM, Tobal K. Polymorphisms and haplotypes in multidrug resistance 1 (MDR1) gene and their association with clinical outcome of some Iraqi patients with acute leukemia. Iraqi J Biotechnol. 2017;16(3):200-8.
  10. Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97(1):89-94. [DOI:10.1182/blood.V97.1.89] [PMID]
  11. Liang DC, Shih LY, Hung IJ, Yang CP, Chen SH, Jaing TH, et al. Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia. Cancer. 2002;94(12):3292-8. [DOI:10.1002/cncr.10598] [PMID]
  12. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et al. 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(12):4326-35. [DOI:10.1182/blood.V99.12.4326] [PMID]
  13. Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17(9):1738-52. [DOI:10.1038/sj.leu.2403099] [PMID]
  14. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650-65. [DOI:10.1038/nrc1169] [PMID]
  15. Yusoff YM, Seman ZA, Othman N, Kamaluddin NR, Esa E, Zulkiply NA, et al. Identification of FLT3 and NPM1 Mutations in Patients with Acute Myeloid Leukaemia. Asian Pac J Cancer. 2019;20(6):1749. [PMID] [PMCID] [DOI:10.31557/APJCP.2019.20.6.1749]
  16. Bhattacharyya J, Nath S, Saikia KK, Saxena R, Sazawal S, Barman MP, et al. Prevalence and Clinical Significance of FLT3 and NPM1 Mutations in Acute Myeloid Leukaemia Patients of Assam, India. Indian J Hematol Blood Transfus. 2018;34(1):32-42. [PMID] [PMCID] [DOI:10.1007/s12288-017-0821-0]
  17. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001; 97(8):2434-9. [DOI:10.1182/blood.V97.8.2434] [PMID]
  18. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100 (5):1532-42. [DOI:10.1182/blood-2002-02-0492] [PMID]
  19. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12(9). [DOI:10.1038/sj.leu.2401130] [PMID]
  20. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. 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(6):1752-9. [DOI:10.1182/blood.V98.6.1752] [PMID]
  21. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, et al. 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(1):59-66. [DOI:10.1182/blood.V100.1.59] [PMID]
  22. Nasilowska-Adamska B SI, Paluszewska M, Malinowska I, Jedrzejczak WW, Warzocha K. FLT3-ITD and MLL-PTD influence the expression of MDR-1, MRP-1, and BCRP mRNA but not LRP mRNA assessed with RQ-PCR method in adult acute myeloid leukemia. Ann Hematol. 2014;93(4):577-93. [DOI:10.1007/s00277-013-1898-7] [PMID]
  23. Galimberti S, Rossi A, Palumbo GA, Morabito F, Guerrini F, Vincelli I, et al. FLT3 mutations do not influence MDR-1 gene expression in acute myeloid leukemia. Anticancer Res. 2003;23(4): 3419-26.
  24. Xu B, Song XY, Li L, Xu WJ, Tang JH. [The significance of quantification of MDR1 and WT1 gene expression in acute myeloid leukemia]. Chinese J Intern Med. 2008;47(3):221-4.
  25. Farawela HM, Khorshied MM, Kassem NM, Kassem HA, Zawam HM. The clinical relevance and prognostic significance of adenosine triphosphate ATP-binding cassette (ABCB5) and multidrug resistance (MDR1) genes expression in acute leukemia: an Egyptian study. J Cancer Res Clin Oncol. 2014;140(8):1323-30. [DOI:10.1007/s00432-014-1694-3] [PMID]
  26. Kussick S, Stirewalt D, Yi H, Sheets K, Pogosova-Agadjanyan E, Braswell S, et al. A distinctive nuclear morphology in acute myeloid leukemia is strongly associated with loss of HLA-DR expression and FLT3 internal tandem duplication. Leukemia. 2004;18(10):1591-8. [DOI:10.1038/sj.leu.2403458] [PMID]
  27. Park BG, Chi HS, Jang S, Park CJ, Kim DY, Lee JH, et al. Association of cuplike nuclei in blasts with FLT3 and NPM1 mutations in acute myeloid leukemia. Ann Hematol. 2013;92(4):451-7. [DOI:10.1007/s00277-012-1645-5] [PMID]
  28. Zhu H-H, Liu Y-R, Jiang H, Lu J, Qin Y-Z, Jiang Q, et al. CD34 expression on bone marrow blasts is a novel predictor of poor prognosis independent of FlT3-ITD in acute myeloid leukemia with the NPM1-mutation. Leukemia Res. 2013;37(6):624-30. [DOI:10.1016/j.leukres.2013.02.007] [PMID]
  29. Wang L, Xu WL, Meng HT, Qian WB, Mai WY, Tong HY, et al. FLT3 and NPM1 mutations in Chinese patients with acute myeloid leukemia and normal cytogenetics. J Zhejiang Univ Sci B. 2010;11(10):762-70. [DOI:10.1631/jzus.B1000052] [PMID] [PMCID]
  30. Notopuro PB, Nugraha J, Utomo B, Notopuro H. The Association of FLT3-ITD Gene Mutation with Bone Marrow Blast Cell Count, CD34, Cyclin D1, Bcl-xL and hENT1 Expression in Acute Myeloid Leukemia Patients. Iran J Pathol. 2020;15(4):306-12. [PMID] [PMCID] [DOI:10.30699/ijp.2020.122579.2328]
  31. Fe Joibi K, Ibrahim S, Shafii NF, Mat Jusoh SA, Mustaffa R, Johan MF, et al. Clinical and Laboratory Findings of Cuplike Nuclei in Blasts with FLT3 Mutation in Pediatric Acute Myeloid Leukemia: A Case Report. Iran J Pediatr Hematol Oncol. 2019;9(4):271-5. [DOI:10.18502/ijpho.v9i4.1577]
  32. Kroschinsky FP, Schakel U, Fischer R, Mohr B, Oelschlaegel U, Repp R, et al. Cuplike acute myeloid leukemia: new disease or artificial phenomenon? Haematologica. 2008;93(2):283-6. [DOI:10.3324/haematol.11669] [PMID]
  33. Chen W, Konoplev S, Medeiros LJ, Koeppen H, Leventaki V, Vadhan-Raj S, et al. Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation. Cancer. 2009;115(23):5481-9. [DOI:10.1002/cncr.24610] [PMID] [PMCID]