Hematopoietic progenitor kinase 1 inhibitor BGB-15025 induces apoptosis in acute myeloid leukemia cells through the cell cycle pathway and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway signaling axis

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy originating from the malignant clonal proliferation of hematopoietic stem/progenitor cells and is associated with a poor prognosis. Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a member of the MAP4K family, plays a critical role in immunomodulation and oncogenesis. Previous studies have highlighted its pro-oncogenic function in AML, suggesting its potential as both a prognostic marker and therapeutic target. This study aimed to investigate the anti-AML effects of the novel HPK1 inhibitor BGB-15025. We utilized preclinical models, including AML cell lines, primary patient-derived cells, and MV4-11 xenograft mice. Mechanistic investigations were conducted using RNA sequencing and Western blot analysis. BGB-15025 exerted potent cytotoxicity against AML cells and primary progenitors, inducing apoptosis and G0/G1 cell cycle arrest via downregulation of cyclin D1-cyclin-dependent kinase 4 and upregulation of P21. The inhibitor suppressed mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling through reduced phosphorylation of P38 and ERK. In-vivo studies demonstrated a reduced leukemia burden in xenograft models. This study is the first to elucidate that BGB-15025 triggers AML apoptosis through cell cycle blockade and MAPK pathway inhibition, thereby proposing a novel precision therapeutic strategy with significant clinical translational value.