In previous studies, we have shown that severe MPN and myelofibrosis are induced by TpoR W515A mutant via the cytosolic TpoR tyrosine (Y626) that connects to the shc-ras-MEK-ERK1/2 pathway 9, and that the same tyrosine residue was required for down-modulation of TpoR in JAK2 V617F by excessive ERK1/2 and STAT3 activation, again linked to severe MPN 32. The gene discussed is JAK2; the disease is myelofibrosis.