Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia

  • Yunus, Noraini Mat (Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Johan, Muhammad Farid (Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Al-Jamal, Hamid Ali Nagi (Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Husin, Azlan (Haemato-Oncology Unit, Department of Internal Medicine, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Hussein, Abdul Rahim (Advanced Medical And Dental Institute, Universiti Sains Malaysia) ;
  • Hassan, Rosline (Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia)
  • Published : 2015.07.13
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor gene may promote proliferation via activation of multiple signaling pathways. FLT3-internal tandem duplication (FLT3-ITD) is the most common gene alteration found in patients diagnosed with acute myeloid leukaemia (AML) and has been associated with poor prognosis. Materials and Methods: We performed mutational analysis of exons 14-15 and 20 of the FLT3 gene in 54 AML patients using PCR-CSGE (conformational sensitive gel electrophoresis) followed by sequencing analysis to characterise FLT3 mutations in adult patients diagnosed with AML at Hospital USM, Kelantan, Northeast Peninsular Malaysia. Results: FLT3 exon 14-15 mutations were identified in 7 of 54 patients (13%) whereas no mutation was found in FLT3 exon 20. Six ITDs and one non-ITD mutation were found in exon 14 of the juxtamembrane (JM) domain of FLT3. FLT3-ITD mutations were associated with a significantly higher blast percentage (p-value = 0.008) and white blood cell count (p-value = 0.023) but there was no significant difference in median overall survival time for FLT3-ITD+/FLT3-ITD- within 2 years (p-value = 0.374). Conclusions: The incidence of FLT3-ITD in AML patients in this particular region of Malaysia is low compared to the Western world and has a significant association with WBC and blast percentage.

Keywords

References

  1. Abu-Duhier FM, Goodeve AC, Wilson GA, et al (2001). Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol, 113, 983-8. https://doi.org/10.1046/j.1365-2141.2001.02850.x
  2. Ahmad F, Mandava S, Das BR (2010). Analysis of FLT3-ITD and FLT3-Asp835 mutations in de novo acute myeloid leukemia: evaluation of incidence, distribution pattern, correlation with cytogenetics and characterization of internal tandem duplication from Indian population. Cancer Invest, 28, 63-73. https://doi.org/10.3109/07357900903095649
  3. Betz BL, Hess JL (2010). Acute myeloid leukemia diagnosis in the 21st century. Arch Pathol Lab Med, 134, 1427-33.
  4. 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.
  5. Feng JH, Guo XP, Chen YY, et al (2012). Prognostic significance of IDH1 mutations in acute myeloid leukemia: a meta-analysis. Am J Blood Res, 2, 254-64.
  6. Frohling S, Schlenk RF, Breitruck J, et al (2002). 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, 100, 4372-80. https://doi.org/10.1182/blood-2002-05-1440
  7. Gulley ML, Shea TC, Fedoriw Y (2010). Genetic tests to evaluate prognosis and predict therapeutic response in acute myeloid leukemia. J Mol Diagn, 12, 3-16. https://doi.org/10.2353/jmoldx.2010.090054
  8. Karabacak BH, Erbey F, Bayram I, et al (2010). Fms-like tyrosine kinase 3 mutations in childhood acute leukemias and their association with prognosis. Asian Pac J Cancer Prev, 11, 923-7.
  9. Kiyoi H, Ohno R, Ueda R, et al (2002). Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene, 21, 2555-63. https://doi.org/10.1038/sj.onc.1205332
  10. Kottaridis PD, Gale RE, Frew ME, et al (2001). 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, 98, 1752-9. https://doi.org/10.1182/blood.V98.6.1752
  11. Liang DC, Shih LY, Hung IJ, et al (2003). FLT3-TKD mutation in childhood acute myeloid leukemia. Leukemia, 17, 883-6. https://doi.org/10.1038/sj.leu.2402928
  12. Meshinchi S, Stirewalt DL, Alonzo TA, et al (2008). Structural and numerical variation of FLT3/ITD in pediatric AML. Blood, 111, 4930-3. https://doi.org/10.1182/blood-2008-01-117770
  13. Schnittger S, Schoch C, Dugas M, et al (2002). 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, 100, 59-66. https://doi.org/10.1182/blood.V100.1.59
  14. Shahab S, Shamsi TS, Ahmed N (2013). Prognostic involvement of nucleophosmin mutations in acute myeloid leaukemia. Asian Pac J Cancer Prev, 14, 5615-20. https://doi.org/10.7314/APJCP.2013.14.10.5615
  15. Small D (2006). FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ Program, 178-84.
  16. Smith ML, Hills RK, Grimwade D (2011). Independent prognostic variables in acute myeloid leukaemia. Blood Rev, 25, 39-51. https://doi.org/10.1016/j.blre.2010.10.002
  17. Stirewalt DL, Radich JP (2003). The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer, 3, 650-65. https://doi.org/10.1038/nrc1169
  18. Su L, Gao SJ, Tan YH, et al (2013). Associations between age, cytogenetics, FLT3-ITD, and marrow leukemia cells identified by flow cytometry. Asian Pac J Cancer Prev, 14, 5341-4. https://doi.org/10.7314/APJCP.2013.14.9.5341
  19. Thiede C, Steudel C, Mohr B, et al (2002). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99, 4326-35. https://doi.org/10.1182/blood.V99.12.4326
  20. Wang L, Xu WL, Meng HT, et al (2010). FLT3 and NPM1 mutations in Chinese patients with acute myeloid leukemia and normal cytogenetics. J Zhejiang Univ Sci B, 11, 762-70.
  21. Whitman SP, Maharry K, Radmacher MD, et al (2010). FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood, 116, 3622-6. https://doi.org/10.1182/blood-2010-05-283648
  22. 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
  23. Zeichner SB, Alghamdi S, Elhammady G, et al (2014). Prognostic significance of TP53 mutations and single nucleotide polymorphisms in acute myeloid leukemia: a case series and literature review. Asian Pac J Cancer Prev, 15, 1603-9. https://doi.org/10.7314/APJCP.2014.15.4.1603