How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia

Abstract

Mutations of the FLT3 gene are among the most common genetic aberrations detected in AML and occur mainly as internal tandem duplications (FLT3-ITD). However, the specific sites of FLT3-ITD insertion within FLT3 show marked heterogeneity regarding both biological and clinical features. In contrast to the common assumption that ITD insertion sites (IS) are restricted to the juxtamembrane domain (JMD) of FLT3, 30% of FLT3-ITD mutations insert at the non-JMD level, thereby integrating into various segments of the tyrosine kinase subdomain 1 (TKD1). ITDs inserted within TKD1 have been shown to be associated with inferior complete remission rates as well as shorter relapse-free and overall survival. Furthermore, resistance to chemotherapy and tyrosine kinase inhibition (TKI) is linked to non-JMD IS. Although FLT3-ITD mutations in general are already recognized as a negative prognostic marker in currently used risk stratification guidelines, the even worse prognostic impact of non-JMD-inserting FLT3-ITD has not yet been particularly considered. Recently, the molecular and biological assessment of TKI resistance highlighted the pivotal role of activated WEE1 kinase in non-JMD-inserting ITDs. Overcoming therapy resistance in non-JMD FLT3-ITD-mutated AML may lead to more effective genotype- and patient-specific treatment approaches.

Keywords: FLT3 mutation; acute myeloid leukemia (AML); chemotherapy resistance; internal tandem duplications (FLT3-ITD); non-juxtamembrane domain (non-JMD) insertion site; tyrosine kinase inhibition (TKI).

Figure 1

Structural domains of the FLT3 receptor in schematic representation, adapted from Breitenbuecher et al. [13] and Kayser et al. [5]. Created with BioRender.com (accessed on 25 May 2023).

Figure 2

Schematic overview of oncogenic signaling in FLT3-ITD-mutated AML within FLT3-ITD inserting at non-juxtamembrane domain (non-JMD) sites. Rewiring of oncogenic signaling networks in non-JMD FLT3-ITD drives its oncogenic potential and resistance to chemotherapy and tyrosine kinase inhibitors. The overview of signaling pathways makes no claim of completeness. Created with BioRender.com (accessed on 25 April 2023).