Midostaurin response in AML is shaped by a progenitor-like cell state selectively targeted by SMAC mimetics
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.
Authors
- Mattias Vesterlund (ORCID: https://orcid.org/0000-0001-9471-6592)
- Tom Erkers (ORCID: https://orcid.org/0000-0002-2754-6287)
- Sofia Bengtzén
- Georgios Mermelekas (ORCID: https://orcid.org/0009-0002-1736-9114)
- Nona Struyf (ORCID: https://orcid.org/0000-0002-6975-0753)
- A. B. Bohlin
- L. Pizarro
- Janne Lehtiö (ORCID: https://orcid.org/0000-0002-8100-9562)
- Kerstin Hamberg Levedahl (ORCID: https://orcid.org/0000-0002-2856-0224)
- Henrik Gezelius (ORCID: https://orcid.org/0000-0002-6242-6344)
- Anders Lundmark (ORCID: https://orcid.org/0000-0003-2611-1772)
- Rozbeh Jafari (ORCID: https://orcid.org/0000-0002-3396-4709)
- Päivi Östling (ORCID: https://orcid.org/0000-0001-5501-466X)
- Lukas M. Orre (ORCID: https://orcid.org/0000-0002-0384-1003)
- Jessica Nordlund (ORCID: https://orcid.org/0000-0001-8699-9959)
- Albin Österroos (ORCID: https://orcid.org/0000-0001-8749-7299)
- Chiara Barizza
- Hidde Ploeger
- Sören Lehmann
- Olli Kallioniemi
- Brinton Seashore-Ludlow
Institutions
- Uppsala University (SE)
- University of Helsinki (FI)
- Uppsala University Hospital (SE)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Finland University (FI)
- Institute for Molecular Medicine Finland (FI)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2026-03-11
- DOI
- https://doi.org/10.1038/s41698-026-01363-8
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00