%0 Journal Article
%A Koleci, Naile
%A Wu, Ying
%A Wehner, Niels Anton
%A Rajak, Jovana
%A Mittapalli, Venugopal Rao
%A Mergner, Julia
%A Xiao, Hui
%A Wang, Jun
%A Wahl, Madeleine
%A Bohler, Sheila
%A Aumann, Konrad
%A Häcker, Georg
%A Ramamoorthy, Senthilkumar
%A Boerries, Melanie
%A Kirschnek, Susanne
%A Erlacher, Miriam
%T Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia.
%J Cell death & disease
%V 16
%N 1
%@ 2041-4889
%C London [u.a.]
%I Nature Publishing Group
%M DKFZ-2025-00517
%P 165
%D 2025
%X 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;Ptpn11D61Y/+ 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-XL and MCL-1, were directly regulated by the oncogenic RAS signaling but, in addition, were influenced by microenvironmental signals. While BCL-XL 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-XL inhibition was the most effective in killing myeloid cells in vitro but was insufficient to completely resolve myeloproliferation in vivo.
%K Leukemia, Myelomonocytic, Juvenile: genetics
%K Leukemia, Myelomonocytic, Juvenile: metabolism
%K Leukemia, Myelomonocytic, Juvenile: pathology
%K Apoptosis: genetics
%K Animals
%K Mice
%K Humans
%K bcl-X Protein: metabolism
%K bcl-X Protein: genetics
%K Signal Transduction
%K Myeloid Cell Leukemia Sequence 1 Protein: metabolism
%K Myeloid Cell Leukemia Sequence 1 Protein: genetics
%K Monocytes: metabolism
%K Protein Tyrosine Phosphatase, Non-Receptor Type 11: metabolism
%K Protein Tyrosine Phosphatase, Non-Receptor Type 11: genetics
%K Tumor Microenvironment
%K Granulocytes: metabolism
%K Granulocytes: pathology
%K bcl-X Protein (NLM Chemicals)
%K Myeloid Cell Leukemia Sequence 1 Protein (NLM Chemicals)
%K Protein Tyrosine Phosphatase, Non-Receptor Type 11 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40057493
%R 10.1038/s41419-025-07479-2
%U https://inrepo02.dkfz.de/record/299576