FLT3 mutations in patients with childhood acute lymphoblastic leukemia (ALL)

Abstract

The type III receptor tyrosine kinase FLT3 is of importance in hematopoiesis. FLT3 is a frequently mutated gene in acute myeloid leukemia (AML) as well as prognostic marker. The most common mutation that occurs in patients includes internal tandem duplication (ITD) in the juxtamembrane domain. Point mutations in the kinase domain are also identified in many patients. These mutations result in constitutive activation of receptor as well as uncontrolled activation of survival pathways. Although 30 % of AML patients carry a mutation in FLT3 [2], its expression is not limited to only those patients. It has also been found to be expressed in acute lymphoblastic leukemia (ALL) and several studies identified FLT3 mutations in a portion of ALL patients. This study will identify possible correlation in between FLT3 and childhood ALL patients. With the search criteria depicted in Fig. 1a, we retrieved 12 references that included 1,213 childhood ALL patients with 76 patients (6.3 %) carrying FLT3 mutations (Table S1). All 12 studies described FLT3 mutations. Further review of those references identified 89 patients with MLL-rearrangement and 196 patients with hyperdiploid ALL. Although 6.3 % childhood ALL patients carried FLT3 mutations, 15.7 % of MLL-rearrangement and 14.4 % of hyperdiploid childhood ALL patients carried FLT3 mutations (data not shown). Only 1 % patients carried FLT3-ITD mutations (12/1,213). Childhood ALL patients with MLL-rearrangement displayed an overall odds ratio of 4.17 (95 % Cl = 2.60–9.88, p 0.0001) (Fig. 1b) and patients with hyperdiploid ALL showed an overall odds ratio of 4.03 (95 % Cl = 2.18–7.95, p 0.0001) (Fig. 1c). Studies with FLT3-ITD mutation (Fig. 1d) and FLT3-TKD mutations (Fig. 1e) showed that TKD mutations happened more frequently than ITD mutations. An increased rate of FLT3 mutations was observed in American population (odds ratio = 1.4, 95 % CI = 0.85–2.29), while in Japanese and European population, comparatively lower FLT3 mutations were identified (Fig. 1f). The receptor tyrosine kinase FLT3 is frequently mutated in AML and activating FLT3 mutations cause poor prognosis in this disease [2]. Several FLT3 inhibitors display promising results in clinical trials. Although several studies described presence of FLT3 mutations in childhood ALL, still we have limited knowledge in defining roles of FLT3 mutations. In this study, we carried out a meta-analysis to define the role of FLT3 mutations in childhood ALL. All 12 studies analyzed in this study were mainly from three different populations that cover 1,213 childhood ALL patients. The identification of 76 mutations in these populations suggests that FLT3 mutations in childhood ALL is less frequent than that of in AML. Although about 30 % of FLT3-ITD mutations were reported in AML [2], childhood ALL patients carry only 1 % FLT3-ITD mutations suggesting that targeting FLT3-ITD will not be beneficial in pediatric ALL. It is likely that mutations other than FLT3ITD mutations are more frequent, e. g. FLT3-TKD mutations. However, it is quite difficult to suggest a correlation between FLT3 mutations and ALL prognosis due to the Electronic supplementary material The online version of this article (doi:10.1007/s12032-013-0462-6) contains supplementary material, which is available to authorized users.