Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signaling and characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using MxCre;Ptpn11<sup>D61Y/+</sup> mice, which model human JMML, we show that RAS pathway activation affects apoptosis signaling through cell type-dependent regulation of BCL-2 family members. Apoptosis resistance observed in monocytes and granulocytes was mediated by overexpression of the anti-apoptotic and down-regulation of the pro-apoptotic members of the BCL-2 family. Two anti-apoptotic proteins, BCL-X<sub>L</sub> and MCL-1, were directly regulated by the oncogenic RAS signaling but, in addition, were influenced by microenvironmental signals. While BCL-X<sub>L</sub> and BCL-2 were required for the survival of monocytes, MCL-1 was essential for neutrophils. Interestingly, stem and progenitor cells expressing the oncogenic PTPN11 mutant showed no increased apoptosis resistance. BCL-X<sub>L</sub> inhibition was the most effective in killing myeloid cells in vitro but was insufficient to completely resolve myeloproliferation in vivo.
Authors
- Melanie Boerries (ORCID: https://orcid.org/0000-0002-3670-0602)
- Venugopal R. Mittapalli (ORCID: https://orcid.org/0000-0002-7056-8190)
- Miriam Erlacher (ORCID: https://orcid.org/0000-0002-7261-1447)
- Susanne Kirschnek (ORCID: https://orcid.org/0000-0001-7771-7817)
- Naile Koleci
- Konrad Aumann (ORCID: https://orcid.org/0000-0001-8178-1571)
- Julia Mergner (ORCID: https://orcid.org/0000-0002-4332-1280)
- Senthilkumar Ramamoorthy (ORCID: https://orcid.org/0000-0003-3468-4247)
- Georg Häcker (ORCID: https://orcid.org/0000-0003-1058-5746)
- Sheila Bohler (ORCID: https://orcid.org/0000-0001-8860-9424)
- Jun Wang (ORCID: https://orcid.org/0000-0003-2509-9599)
- Hui Xiao (ORCID: https://orcid.org/0000-0001-7990-9206)
- Ying Wu (ORCID: https://orcid.org/0000-0002-6095-1524)
- Madeleine Wahl
- Jovana Rajak (ORCID: https://orcid.org/0009-0007-0229-8583)
- Niels Anton Wehner
Institutions
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- Universität Ulm (DE)
- University Medical Center Freiburg (DE)
- German Cancer Society (DE)
- Institute of Medical Microbiology and Hygiene (DE)
- University Hospital Ulm (DE)
- Technical University of Munich (DE)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-03-08
- DOI
- https://doi.org/10.1038/s41419-025-07479-2
- Citations
- 2
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 3.54
Funders
- Deutsche Forschungsgemeinschaft