Oncogenic and microenvironmental signals drive cell type-specific apoptosis resistance in juvenile myelomonocytic leukemia

ABSTRACT: Juvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signalling and is characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using Mx-Cre;PTPN11D61Y mice, which reflect human JMML, we show that RAS pathway activation affects apoptosis signalling 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 signalling 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 did not display any increased apoptosis resistance. BCL-XL inhibition was the most effective in killing myeloid cells in vitro but was not sufficient to completely resolve myeloproliferation in vivo.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, Bone Marrow

DISEASE(S): Juvenile Myelomonocytic Leukemia

SUBMITTER: Julia Mergner  

LAB HEAD: Julia Mergner

PROVIDER: PXD055845 | Pride | 2025-05-07

REPOSITORIES: Pride