1. ¹Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg
2. ²Department of Biochemistry; Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse, Aachen, Germany
3. ³Department of Pediatrics, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse, Aachen, Germany

Correspondence: Dr S Haan, Life Sciences Research Unit, University of Luxembourg, Campus Limpertsberg, 162A, Avenue de la Faïencerie, Luxembourg L-1511, Luxembourg. E-mails: serge.haan@uni.lu; Dr C Haan, claude.haan@uni.lu

⁴These authors contributed equally to this work.

Received 1 December 2008; Revised 24 April 2009; Accepted 11 May 2009; Published online 22 June 2009.

Abstract

Recently, mutations in the gene of Janus kinase 2 (Jak2) were discovered in patients suffering from chronic myeloproliferative disorders (MPD) and leukemia. As suppressors of cytokine signaling (SOCS) proteins are potent feedback inhibitors of Jak-mediated signaling, we investigated their role in signal transduction through constitutively active Jak2 mutants. We selected two mutants, Jak2-V617F and Jak2-K539L, found in patients with MPDs and Jak2-T875N identified in acute megakaryoblastic leukemia. We found SOCS family members to be induced through Jak2-V617F in human leukemia cell lines expressing the mutant allele and in stable HEK transfectants inducibly expressing constitutively active Jak2 mutants. SOCS proteins were recruited to the membrane and bound to the constitutively active Jaks. In contrast to wild-type Jak2, the mutant proteins were constitutively ubiquitinated and degraded through the proteasome. Taken together, we show a SOCS-mediated downregulation of the constitutively active, disease-associated mutant Jak2 proteins. Furthermore, a threshold level of mutant Jak expression has to be overcome to allow full cytokine-independent constitutive activation of signaling proteins, which may explain progression to homozygocity in MPDs as well as gene amplification in severe phenotypes and leukemia.