Concomitant targeting of FLT3 and SPHK1 exerts synergistic cytotoxicity in FLT3-ITD⁺ acute myeloid leukemia by inhibiting β-catenin activity via the PP2A-GSK3β axis.

ABSTRACT:

Background

Approximately 25-30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML.

Methods

We performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked

SUBMITTER: Jiang L 

PROVIDER: S-EPMC11304842 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature