SMAD4 and myeloproliferative disorder: Our finding that CALR causes TGF-β expression may be counter intuitive as TGF-β can have an inhibitory effect on tumor cell proliferation (59), but this is counteracted in our MPN cells by downregulation of key TGF-β signaling mediators like Tgfbr1, Tgfbr2, Smad1 and Smad4 together with simultaneous upregulation of SMAD Specific E3 Ubiquitin Protein Ligase 1 (Smurf1) responsible for regulating proteasomal degradation of SMAD1 and SMAD5.