Janus kinase 2(JAK2)V617F-activating mutations (JAK2mu) occur in myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs). Cell lines MB-02, MUTZ-8, SET-2 and UKE-1 carryJAK2V617F and derive from patients with MPD/MDS histories. Challenging the consensus that expression ofJAK2V617F is the sole precondition for cytokine independence in class I cytokine receptor-positive cells, two of four of theJAK2mu cell lines were growth factor-dependent. These cell lines resembledJAK2wt cells regarding JAK2/STAT5 activation: cytokine deprivation effected dephosphorylation, whereas erythropoetin or granulocyte colony-stimulating factor induced phosphorylation of JAK2 and STAT5. Cytokine independence correlated with low expression and cytokine dependence with high expression of the JAK/STAT pathway inhibitorsuppressor of cytokine signaling 2 (SOCS2)suggesting a two-step mechanism for cytokine independence of MPD cells: (i) activation of the oncogeneJAK2V617F and (ii) inactivation of the tumor suppressor geneSOCS2.Confirming that SOCS2 operates as a negative JAK2V617F regulator,SOCS2knockdown induced constitutive STAT5 phosphorylation inJAK2mu cells. CpG island hypermethylation is reported to promoteSOCSgene silencing in malignant diseases. Accordingly, in one of two cytokine-independent cell lines and in two of seven MPD patients, we foundSOCS2hypermethylation associated with reduced promoter access to transcription factors. Our results provide solid evidence thatSOCS2epigenetic downregulation might be an important second step in the genesis of cytokine-independent MPD clones.