CALR acts as a rogue cytokine in the MPNs. Mutant CALR protein is secreted from CALR mutant MPN cells where it binds the TpoR of surrounding cells to enhance downstream JAK/STAT activation. The mutant protein has a much lesser effect on wild-type (WT) hematopoietic cells. Note that it is also possible that this secreted CALR rogue cytokine may also act in an autocrine fashion. sTFRC, soluble TFRC. Professional illustration by Patrick Lane, ScEYEnce Studios.