Interaction between Ras and neurofibromin in healthy and JMML cells. GM-CSF binding to its surface receptor leads to dimerization and recruits Janus kinase 2 (JAK2), which creates docking sites for adapter molecules by phosphorylating tyrosine residues on the β chain. The guanine nucleotide dissociation factor SOS induces guanosine diphosphate (GDP) dissociation from Ras at the plasma membrane. Ras is then free to bind to GTP, which interacts with effectors such as Raf-1 to activate kinase signaling cascades. Neurofibromin negatively regulates growth by accelerating hydrolysis of Ras-GTP to inactive Ras-GDP. Oncogenic point RAS mutations and loss of NF1 contribute to aberrant proliferation and survival in JMML by elevating Ras-GTP levels. JMML cells are hypersensitive to GM-CSF in vitro, and studies in stains of mutant mice suggest that GM-CSF plays a central role in the aberrant growth of Nf1-deficient cells in vivo.