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<p>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<sup>+</sup>CD45RA<sup>+</sup> 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 CD34<sup>hi</sup> cells, underscoring distinct subpopulation vulnerabilities. These findings may point to a biologically relevant mechanism underlying midostaurin resistance.</p>

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Midostaurin response in AML is shaped by a progenitor-like cell state selectively targeted by SMAC mimetics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Nona Struyf,
  • Henrik Gezelius,
  • Anders Lundmark,
  • Chiara Barizza,
  • Hidde Ploeger,
  • Lucia Rico Pizarro,
  • Mattias Vesterlund,
  • Georgios Mermelekas,
  • Albin Österroos,
  • Anna Bohlin,
  • Sofia Bengtzén,
  • Kerstin Hamberg Levedahl,
  • Rozbeh Jafari,
  • Lukas M. Orre,
  • Janne Lehtiö,
  • Päivi Östling,
  • Brinton Seashore-Ludlow,
  • Jessica Nordlund,
  • Sören Lehmann,
  • Olli Kallioniemi,
  • Tom Erkers

摘要

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.