SOCS2: inhibitor of JAK2V617F-mediated signal transduction

• Published in: Leukemia Vol. 22; no. 12; pp. 2169 - 2175
• Main Authors: Quentmeier, H, Geffers, R, Jost, E, MacLeod, R A F, Nagel, S, Röhrs, S, Romani, J, Scherr, M, Zaborski, M, Drexler, H G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2008; Nature Publishing Group
• Subjects: Apoptosis - physiology; Bone marrow; Cancer Research; Cell activation; Cell culture; Cell Division - physiology; Cell Line; Cellular signal transduction; Chronic Disease; Colony-stimulating factor; Control; CpG islands; Critical Care Medicine; Cytokines; Cytokines - metabolism; Dephosphorylation; Deprivation; Epigenesis, Genetic - physiology; Epigenetics; Gene Expression Regulation, Leukemic; Gene mutations; Gene silencing; Gene Silencing - physiology; Genes; Genetic aspects; Granulocyte colony-stimulating factor; Granulocytes; Growth factors; Health aspects; Hematology; Humans; Hybridization; Inactivation; Intensive; Internal Medicine; Janus kinase; Janus kinase 2; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Kinases; Leukemia; Leukocytes (granulocytic); Medicine; Medicine & Public Health; Methylation; Microorganisms; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myeloproliferative diseases; Myeloproliferative disorders; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; Myeloproliferative Disorders - pathology; Oncology; original-article; Phosphorylation; Physiological aspects; Point Mutation; Protein kinases; Signal transduction; Signal Transduction - physiology; Stat5 protein; STAT5 Transcription Factor - metabolism; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Transcription factors; Tumor suppressor genes; Tumors; Germany; Aachen Germany; MPD; SOCS2; STAT5; JAK2
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2008.226

Janus kinase 2 ( JAK2 )V617F-activating mutations ( JAK2 mu) occur in myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs). Cell lines MB-02, MUTZ-8, SET-2 and UKE-1 carry JAK2 V617F and derive from patients with MPD/MDS histories. Challenging the consensus that expression of JAK2 V617F is the sole precondition for cytokine independence in class I cytokine receptor-positive cells, two of four of the JAK2 mu cell lines were growth factor-dependent. These cell lines resembled JAK2 wt 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 inhibitor suppressor of cytokine signaling 2 ( SOCS2) suggesting a two-step mechanism for cytokine independence of MPD cells: (i) activation of the oncogene JAK2 V617F and (ii) inactivation of the tumor suppressor gene SOCS2 . Confirming that SOCS2 operates as a negative JAK2V617F regulator, SOCS2 knockdown induced constitutive STAT5 phosphorylation in JAK2 mu cells. CpG island hypermethylation is reported to promote SOCS gene silencing in malignant diseases. Accordingly, in one of two cytokine-independent cell lines and in two of seven MPD patients, we found SOCS2 hypermethylation associated with reduced promoter access to transcription factors. Our results provide solid evidence that SOCS2 epigenetic downregulation might be an important second step in the genesis of cytokine-independent MPD clones.