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@ARTICLE{Koleci:299576,
author = {N. Koleci and Y. Wu and N. A. Wehner and J. Rajak and V. R.
Mittapalli and J. Mergner and H. Xiao and J. Wang and M.
Wahl and S. Bohler and K. Aumann and G. Häcker and S.
Ramamoorthy and M. Boerries and S. Kirschnek and M.
Erlacher$^*$},
title = {{O}ncogenic and microenvironmental signals drive cell type
specific apoptosis resistance in juvenile myelomonocytic
leukemia.},
journal = {Cell death $\&$ disease},
volume = {16},
number = {1},
issn = {2041-4889},
address = {London [u.a.]},
publisher = {Nature Publishing Group},
reportid = {DKFZ-2025-00517},
pages = {165},
year = {2025},
abstract = {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.},
keywords = {Leukemia, Myelomonocytic, Juvenile: genetics / Leukemia,
Myelomonocytic, Juvenile: metabolism / Leukemia,
Myelomonocytic, Juvenile: pathology / Apoptosis: genetics /
Animals / Mice / Humans / bcl-X Protein: metabolism / bcl-X
Protein: genetics / Signal Transduction / Myeloid Cell
Leukemia Sequence 1 Protein: metabolism / Myeloid Cell
Leukemia Sequence 1 Protein: genetics / Monocytes:
metabolism / Protein Tyrosine Phosphatase, Non-Receptor Type
11: metabolism / Protein Tyrosine Phosphatase, Non-Receptor
Type 11: genetics / Tumor Microenvironment / Granulocytes:
metabolism / Granulocytes: pathology / bcl-X Protein (NLM
Chemicals) / Myeloid Cell Leukemia Sequence 1 Protein (NLM
Chemicals) / Protein Tyrosine Phosphatase, Non-Receptor Type
11 (NLM Chemicals)},
cin = {FR01},
ddc = {570},
cid = {I:(DE-He78)FR01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40057493},
doi = {10.1038/s41419-025-07479-2},
url = {https://inrepo02.dkfz.de/record/299576},
}