Identification of cell-extrinsic pro-survival factors in JMML

Abstract

Juvenile myelomonocytic leukemia (JMML) is an aggressive early childhood myeloid leukemia caused by constitutive RAS pathway activation, with the most severe form showing a mutation in the PTPN11 gene/SHP2 tyrosine phosphatase. Our previous work has shown that expression of an oncogenic SHP2 protein in the murine hematopoietic system results in apoptosis resistance of the leukemic myeloid compartment and that environmental signals further improve cell survival. Mass spectrometry revealed CD74 and CD11b as candidate molecules possibly contributing to the apoptosis resistance. CD74 is a surface receptor promoting cell proliferation and survival. Integrin CD11b regulates adhesion and migration. We investigated which JMML cells express CD74 and CD11b and if inhibition of either molecule promotes survival in these cells (MxCre;Ptpn11D61Y/+). We found CD74 upregulated in leukemic neutrophils, macrophages and dendritic cells but not in JMML stem and progenitor cells. CD11b was upregulated specifically in monocytes. However, in vitro blocking of either CD74 or CD11b did not result in apoptosis. We therefore hypothesize that both molecules play other, e.g. immunomodulatory functions in JMML.