NPJ precision oncology · 2026
Midostaurin response in AML is shaped by a progenitor-like cell state selectively targeted by SMAC mimetics.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Struyf Nona, Gezelius Henrik, Lundmark Anders, Barizza Chiara, Ploeger Hidde, Rico Pizarro Lucia, Vesterlund Mattias, Mermelekas Georgios, Österroos Albin, Bohlin Anna, Bengtzén Sofia, Hamberg Levedahl Kerstin, Jafari Rozbeh, Orre Lukas M, Lehtiö Janne, Östling Päivi, Seashore-Ludlow Brinton, Nordlund Jessica, Lehmann Sören, Kallioniemi Olli, Erkers Tom
Аннотация
FLT3-mutated acute myeloid leukemia (AML) remains difficult to treat due to frequent resistance to FLT3 inhibitors like midostaurin. In this study, we observed a progenitor-like CD38+CD45RA+ leukemic cell population that may be associated with midostaurin resistance. Midostaurin-resistant cells display disrupted membrane architecture and a shift in signaling from STAT5 to PI3K/AKT, favoring survival over apoptosis. Functional drug testing was consistent with clinical response to midostaurin, and together with multi-omic profiling, including single-cell and proteomic analyses, indicated the presence and relevance of this resistant phenotype. Drug combination screening revealed that co-targeting with SMAC mimetics restores apoptotic competence and selectively depletes the resistant population when combined with midostaurin. In contrast, venetoclax combinations preferentially affected CD34hi cells, underscoring distinct subpopulation vulnerabilities. These findings may point to a biologically relevant mechanism underlying midostaurin resistance.