Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients

Abstract

Genomic aberrations of Fms-like tyrosine kinase 3 (FLT3), including internal tandem duplication (ITD) and point mutations, have been demonstrated in 25–30% of adults acute myeloid leukemia (AML) and are markers of poor prognosis. FLT3/ITD and D835 mutations were analyzed in 194 Chinese patients with acute leukemia and myelodysplastic syndromes (MDS) by polymerase chain reaction (PCR). FLT3/ITDs and D835 mutations were found in 25.9 and 6.3% of 143 AML patients, respectively. Two patients showed both ITD and point mutations. Among the FAB subtypes of AML, the rate of FLT3 aberration was significantly higher in M3 and M5. However, neither aberrations was found in 25 patients with acute lymphoblastic leukemia (ALL), 2 acute hybrid leukemia, 17 MDS and 7 chronic myeloid leukemia in blast crisis (CML-BC). FLT3/ITD was associated to leukocytosis and lower complete remission (CR) rate, and was more prevalent in patients with normal karyotype. In contrast, D835 mutation was not associated with leukocytosis or low CR rate. Our results confirm that FLT3 activating mutations also occur in a significant percentage in Chinese AML patients. FLT3/ITD⁺ patients treated with standard induction regimen could achieve lower complete remission rates compared with patients not harboring this defect. Early detection of FLT3 mutations and an intensification of induction therapy might thus be useful for this group of patients to overcome the poor prognosis.

Introduction

Fms-like tyrosine kinase 3 (FLT3), a new member of the receptor tyrosine kinase (RTK) III subfamily, was originally identified by its expression in hematopoietic stem/progenitor cells, and its importance in normal lymphohematopoietic stem cell function is now well illustrated [1]. Upon binding to the extracellular domain of FLT3, FLT3 ligand (FL) induces conformational changes and stabilizes receptor dimerization. The receptor dimerization brings the kinase domains into close proximity, and subsequent autophosphorylation of tyrosine residues further increases kinase activities. Activated RTKs then phosphorylate and/or bind multiple signal molecules leading to cell proliferation, differentiation or survival. Hence, alteration to the structure and/or expression of RTKs can result in tumorigenesis. Furthermore, acute myeloid leukemia (AML) cells have been shown to express FLT3, and exogenous FL can enhance their survival and proliferative response [2]. Therefore, alterations in FLT3 signaling through either aberrant FL expression or through gain-of-function mutations in the FLT3 gene itself could potentially contribute to leukemogenesis. Two types of FLT3 activating mutations have been reported in leukemia patients: internal tandem duplication (ITD) and D835Y mutation. Both mutations can result in constitutive FLT3 activation [3].

There have been several reports, describing activating mutations of the FLT3 gene. In this study, we analyzed the prevalence of the two types of FLT3 activating mutations in 194 Chinese acute leukemia patients. Our findings suggest that FLT3/ITD and D835 mutation also occurs in a significant percentage of Chinese adult AML patients.