Abstract
FLT3 internal tandem duplication (FLT3-ITD) is a frequent mutation in acute myeloid leukemia (AML) and remains a strong prognostic factor due to high rate of disease recurrence. Several FLT3-targeted agents have been developed, but determinants of variable responses to these agents remain understudied. Here, we investigated the role FLT3-ITD allelic ratio (ITD-AR), ITD length, and associated gene expression signatures on FLT3 inhibitor response in adult AML. We performed fragment analysis, ex vivo drug testing, and next generation sequencing (RNA, exome) to 119 samples from 87 AML patients and 13 healthy bone marrow controls. We found that ex vivo response to FLT3 inhibitors is significantly associated with ITD-AR, but not with ITD length. Interestingly, we found that the HLF gene is overexpressed in FLT3-ITD+ AML and associated with ITD-AR. The retrospective analysis of AML patients treated with FLT3 inhibitor sorafenib showed that patients with high HLF expression and ITD-AR had better clinical response to therapy compared to those with low ITD-AR and HLF expression. Thus, our findings suggest that FLT3 ITD-AR together with increased HLF expression play a role in variable FLT3 inhibitor responses observed in FLT3-ITD+ AML patients.
Highlights
Abbreviations AML Acute myeloid leukemia allelic ratio (AR) Allelic ratio BM Bone marrow CI Confidence interval drug sensitivity and resistance testing (DSRT) Drug sensitivity and resistance testing DSS Drug sensitivity score FDR False discovery rate FLT3 FMS-like tyrosine kinase 3 Hepatic Leukemia Factor (HLF) Hepatic leukemia factor ITD Internal tandem duplication qPCR Quantitative polymerase chain reaction R/R Relapsed or refractory selective drug sensitivity scores (sDSS) Selective drug sensitivity score WT Wild type
We found no correlation between ITD allelic ratio (ITD-AR) and ITD length, weak positive correlation existed between ITD-AR and BM blast percentage (Fig. S1)
These analyses provide evidence that R/R FLT3-ITD+ samples frequently have higher ITD-AR and blast counts compared to diagnostic samples, whereas patients with long ITD mutations have higher leukocyte counts compared to patients with short ITD (< 45 bp) regardless of disease stage
Summary
Abbreviations AML Acute myeloid leukemia AR Allelic ratio BM Bone marrow CI Confidence interval DSRT Drug sensitivity and resistance testing DSS Drug sensitivity score FDR False discovery rate FLT3 FMS-like tyrosine kinase 3 HLF Hepatic leukemia factor ITD Internal tandem duplication qPCR Quantitative polymerase chain reaction R/R Relapsed or refractory sDSS Selective drug sensitivity score WT Wild type. The aim of this study was to assess whether (i) FLT3-ITD allelic ratio (AR) and ITD mutation length and/or (ii) transcriptomic features, are associated with ex vivo and clinical responses to FLT3 inhibitors in adult AML.
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