c-MPL is required for megakaryopoiesis in iPS-derived hematopoietic stem cells harboring CALR mutations. (A) Bar graph represents relative CD42b cell number induced from hematopoietic stem cells infected with indicated shRNA and cultured in TPO-free media. Note that c-MPL sh4 exhibits equivalent knock-down capacity to sh1-3 in UT-7/TPO CALR Del52 cells (not shown). (B) A model for JAK2 downstream activation by mutant CALR proteins. Mutant CALR interacts with c-MPL and presumably induces a structural change sufficient for JAK2 activation, leading to the phosphorylation of downstream molecules including ERK1/2 and STAT5. Note that mutant CALR and c-MPL may interact indirectly.