Deletions in FLT-3 juxtamembrane domain define a new class of pathogenic mutations: case report and systematic analysis

The FMS-like tyrosine kinase 3 (FLT-3) is the most frequently mutated gene in acute myeloid leukemia (AML), a high-risk feature, and now the target of tyrosine kinase inhibitors (TKIs), which are approved and in development. The most common mutation is the internal tandem duplication (ITD). We present a novel mutation, FLT-3/Q575 Delta, identified in a patient with AML through next-generation sequencing (NGS). This mutation is activating, drives downstream signaling comparable to FLT-3/ITD, and can be targeted using available FLT-3 TKIs. We present the results of a systematic analysis that identified Y572 Delta, E573 Delta, and S574 Delta as similarly activating and targetable deletions located in the FLT-3 juxtamembrane domain (JMD). These mutations target key residues in the JMD involved in the interactions within FLT-3 that regulate its activation. Our results suggest a new class of FLT-3 mutations that may have an impact on patient care and highlight the increasing importance of a systematic understanding of FLT-3 mutations other than ITD. It is likely that, as NGS becomes more commonly used in the diagnosis of patients with AML, these and other activating mutations will be discovered with increasing frequency.

Automated summary

FLT-3 is the most frequently mutated gene in AML, and FLT-3/Q575 Delta is a novel activating mutation that can be targeted by existing FLT-3 TKIs. Additionally, Y572 Delta, E573 Delta, and S574 Delta in FLT-3's JMD are also activating mutations that can be targeted. This study highlights the importance of systematic understanding of FLT-3 mutations beyond ITD, as more activating mutations may be discovered with the increasing use of NGS in AML diagnosis.