Proposed model of signaling pathways relevant to RAS-WT or RAS -mutated IgH-CRLF2-r ALL cells. STAT signaling is largely dispensable regardless of RAS mutation status. (Left) In RAS-WT/JAK2-mutated-IgH-CRLF2-r ALL cells, the IL7R/CRLF2/JAK2/JAK1 complex plays a major role in relaying signals toward downstream RAS/mTORC1 pathways. Adaptor molecules (CRKL and RAPGEF), which relay RTK-mediated signals (eg, FLT3), and modulators of the RAS/mTORC1 pathway (GRB2, SOS1, PTPN11, and SHOC2) are necessary for cell growth. (Right) By contrast, they are largely dispensable in RAS-mutated IgH-CRLF2-r ALL cells. Furthermore, RAS-mutated ALL cells depend less on the IL7R/CRLF2/JAK2/JAK1 complex than do RAS-WT cells. Signaling pathways targeted by ruxolitinib, gilteritinib, and trametinib are also depicted. Phosphorylation of S6 protein at S235/236 is mediated by both ERK and mTORC1 activity,⁴⁰ while S6 phosphorylation at S240/244 is primarily mTORC1-dependent.⁴⁰ The upstream RTK pathway is reportedly activated by MEK inhibition.⁶¹