CBL and chronic myelomonocytic leukemia: SH2B3 directly binds to wild-type JAK2 and JAK2 V617F and decreases their autophosphorylation and downstream signaling through STAT5 (signal transducer and activator of transcription factor 5), MAPK (mitogen-activated protein kinase)/ERK (extracellular signal–regulated kinase) and the PI3K (phosphoinositide-3 kinase)/AKT pathways.78SH2B3 mutations are seen in ~5–7% of CMML patients and may co-occur with CBL mutations, suggesting a collaborative effect.79 These mutations, again, lack an independent prognostic effect on disease outcomes.