Clinical relevance ofFLT3gene abnormalities in Brazilian patients with infant leukemia

Abstract

Infant leukemia (IL) is characterised by the presence of MLL rearrangements and a poor outcome. FLT3 gene is consistently highly expressed in MLL+ patients. To correlate the clinical aspects of IL with FLT3 sequence alterations, we have analysed 159 children included in the Brazilian Collaborative Study Group of Infant Acute Leukemia. FLT3-D835 mutations and FLT3-ITD were detected by PCR-RFLP assay and standard PCR amplification, respectively. Mean age at diagnosis was 11.3 months. Overall, 7.5% (ITDs n=6 and D835 n=6) of patients contained FLT3 mutations. FLT3 mutated cases exhibited significantly higher white blood cells (WBC) than wild-type patients (p=0.013). Median overall survival time was 9.2 months (SE 3.3, 95% CI 2.8-15.6). Variables with significant poorer outcomes were age<6 months (p=0.0043), MLL+ (p=0.0292), AML subtype (p=0.0008), high WBC (p=0.0179) and FLT3-D835 mutation (p=0.042). The concomitant presence of FLT3 and MLL abnormalities displayed the worst survival (p=0.0032). Cox regression analysis, with survival as endpoint, showed that leukemia subtype and WBC were independent prognostic factors. Although FLT3 mutations were not a frequent genetic abnormality in this cohort, they might be prognostically important in IL, but this will need to be confirmed in the analyses of larger patient cohorts.

FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

“…on March 21, 2019. by guest www.bloodjournal.org From cells 14 and that secondary oncogenic hits may be required, making FLT3 activation a candidate. [15][16][17][18]21,39,42 The data presented here reveal that expression of the MLL-AF4 fusion oncogene together with FLT3 mutations does not confer either an in vitro proliferative or survival advantage to hESC-derived hemogenic precursors nor to CD45…”

“…This suggests that FLT3-activating mutations promote hESC hematopoietic specification rather than selective proliferation or survival of hESC-emerging hematopoietic derivatives. Several groups have reported the presence of FLT3-TKD mutations in MLL-rearranged ALLs, 15,16,39 whereas others have shown that FLT3 mutations in MLL-rearranged ALLs do not occur. 17,20,21,40,41 High expression of FLT3 is a hallmark step in the pathogenesis of MLL-AF41 ALL, 17 but it has not been resolved whether the constitutive activation of FLT3 in MLL-AF41 ALL is because of the presence of activating FLT3 mutations or simply the result of an increased expression of FLT3.…”

“…13,14 Despite current controversy about the presence of FLT3 gene mutations in MLL-AF41 ALL, [15][16][17]20,21,39 GEP identified the FLT3 gene consistently highly expressed in MLL-AF41 ALL, indicating that FLT3 activation may represent a candidate-cooperating lesion in MLL-AF4-mediated ALL. hESCs and hESC derivatives enable the study of early human development that cannot otherwise be addressed by patient sample analyses or mouse models.…”

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

“…Several groups reported the presence of FLT3/tyrosine kinase domain (TKD) mutations in 3-20% of MLL-rearranged ALLs, 6,[12][13][14] whereas Stam et al 15,16 together with Bardini et al, 17,18 using high-resolution genomic analysis, showed that FLT3 mutations in MLL-rearranged ALLs do not occur. Despite this emerging controversy, FLT3 is consistently highly expressed in MLLrearranged ALL, and therefore it is not fully resolved whether the constitutive activation of FLT3 in MLL-rearranged ALL is due to the presence of activating FLT3 mutations, or simply due to a transcriptional increased expression of FLT3 in an attempt to provide blast cells with survival and proliferative advantage.…”

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

“…Some studies have shown that MLL-r B-ALL harbors FLT3 mutations in 3% to 21% of cases, [76][77][78] whereas others have shown that FLT3 mutations are not present in MLL-r B-ALL. 21,40,[79][80][81] Given that FLT3 is consistently highly expressed in MLL-r B-ALL, increased transcriptional expression of FLT3 rather than activating mutations could represent an important hallmark of MLL-r B-ALL.…”