CXCL7 mediates the survival and differentiation of megakaryocytic leukemia cells through AKT/mTOR signaling Pathway

Acute megakaryocytic leukemia (AMKL) represents a distinct subtype of acute myeloid leukemia (AML), characterized by the predominance of more than 50% blasts from the megakaryocyte lineage. Despite the advancements in understanding of AMKL pathogenesis, the precise mechanisms underlying the aberrant proliferation of dysplastic megakaryoblasts remain largely elusive. In this study, we demonstrate that the CXCL7 gene is markedly overexpressed in both AMKL patients and AMKL cell lines compared to non-AMKL types. CXCL7 interference in AMKL cells induces the cell cycle arrest and differentiation, as evidenced by the elevated expression of megakaryocyte markers, including CD41, CD42b and CD61. CXCL7 overexpression markedly inhibits cell differentiation without affecting cell survival. In addition, CXCR1/2 inhibitor treatment also inhibit cell growth and promote cell differentiation that mimic the CXCL7 knockdown. Mechanistically, RNA sequencing and in vitro analyses indicate that the AKT/mTOR signaling pathway mediates the effects of the CXCL7 gene in AMKL cells. In vivo studies further corroborate these findings, as NOD/SCID mice engrafted with AMKL cells exhibit prolonged survival upon CXCL7 gene knockdown. Our findings elucidate the pivotal role of CXCL7 in regulating cell survival and differentiation in AMKL cells typically, suggesting its potential as a therapeutic target for AMKL treatment.