FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group

Abstract

Genomic DNA from 106 cases of adult de novo acute myeloid leukaemia (AML) was screened by polymerase chain reaction (PCR) and gel electrophoresis for FLT3 internal tandem duplication (ITD) mutations within the juxtamembrane (JM) domain. FLT3 mutations were detected in 14 cases (13.2%) and occurred in FAB types M1 (4 out of 14 cases), M3 (1 out of 10 cases), M4 (5 out of 37 cases) and M5 (4 out of 11 cases). Sequence analysis of four cases with abnormal PCR electrophoretic patterns revealed in frame duplications in the region of exon 11 of between 27 and 111 base pairs. Three are predicted to result in the tandem duplication of adjacent amino acid residues and one to result in a tandem duplication plus insertion of a novel amino acid motif. Statistical analysis showed the FLT3 mutations to be a strong prognostic factor, with patients lacking the mutation surviving significantly longer from diagnosis (mean 29.1 months) than those with an ITD (mean 12.8 months; P = 0.0002). Thirteen of the 14 patients with FLT3 mutations died within 18 months of diagnosis. FLT3 mutations were of prognostic significance in good risk disease (P = 0.04), as well as in patients with standard risk disease (P = 0.0096). This study demonstrates that the FLT3 ITD mutation occurs in a significant percentage of adult AML cases and is an important adverse prognostic factor that appears independent of conventional karyotypic findings.

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

“…Many studies indicate that FLT3-ITD confers a poor prognosis in AML patients by increasing relapse risk and reducing survival. [17][18][19][20][21] More recently, increasing evidence suggests that higher FLT3-ITD to wild-type allelic ratios are associated with poor prognosis. 22 In our patients, FLT3 mutation by itself did not impact DFS.…”

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

“…14 FLT3-ITD is an independent predictor of poor prognosis and is associated with increased relapse risk after chemotherapy, and decreased disease-free survival and overall survival. 6,8,10,15,16 The clinical significance of FLT3-D835 is still unclear. Some studies have shown that FLT3-D835 is associated with shorter disease-free and overall survival.…”

MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells

“…Recent studies have revealed that activating mutations of RTKs frequently occur in acute myelogenous leukemia (AML) patients. For example, internal tandem duplications (ITDs) of the JM domain of FLT3 (FLT3-ITD) are present in 20-30% of de novo AML cases [4]; and approximately 7% of AML patients possess the D835 mutation, a point mutation in the activation loop of the second kinase domain of FLT3 [4]. These mutations result in constitutively activated FLT3 and its downstream signal pathways, and are associated with elevated blast counts, increased relapse rates and poor overall survival in AML [5][6][7][8].…”