TY  - JOUR
AU  - Koleci, Naile
AU  - Wu, Ying
AU  - Wehner, Niels Anton
AU  - Rajak, Jovana
AU  - Mittapalli, Venugopal Rao
AU  - Mergner, Julia
AU  - Xiao, Hui
AU  - Wang, Jun
AU  - Wahl, Madeleine
AU  - Bohler, Sheila
AU  - Aumann, Konrad
AU  - Häcker, Georg
AU  - Ramamoorthy, Senthilkumar
AU  - Boerries, Melanie
AU  - Kirschnek, Susanne
AU  - Erlacher, Miriam
TI  - Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia.
JO  - Cell death & disease
VL  - 16
IS  - 1
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DKFZ-2025-00517
SP  - 165
PY  - 2025
AB  - 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.
KW  - Leukemia, Myelomonocytic, Juvenile: genetics
KW  - Leukemia, Myelomonocytic, Juvenile: metabolism
KW  - Leukemia, Myelomonocytic, Juvenile: pathology
KW  - Apoptosis: genetics
KW  - Animals
KW  - Mice
KW  - Humans
KW  - bcl-X Protein: metabolism
KW  - bcl-X Protein: genetics
KW  - Signal Transduction
KW  - Myeloid Cell Leukemia Sequence 1 Protein: metabolism
KW  - Myeloid Cell Leukemia Sequence 1 Protein: genetics
KW  - Monocytes: metabolism
KW  - Protein Tyrosine Phosphatase, Non-Receptor Type 11: metabolism
KW  - Protein Tyrosine Phosphatase, Non-Receptor Type 11: genetics
KW  - Tumor Microenvironment
KW  - Granulocytes: metabolism
KW  - Granulocytes: pathology
KW  - bcl-X Protein (NLM Chemicals)
KW  - Myeloid Cell Leukemia Sequence 1 Protein (NLM Chemicals)
KW  - Protein Tyrosine Phosphatase, Non-Receptor Type 11 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40057493
DO  - DOI:10.1038/s41419-025-07479-2
UR  - https://inrepo02.dkfz.de/record/299576
ER  -