Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor α homodimers

Tekla Hornakova, Judith Staerk, Yohan Royer, Elisabetta Flex, Marco Tartaglia, Stefan N. Constantinescu, Laurent Knoops, Jean Christophe Renauld

Research output: Contribution to journalArticlepeer-review


Activating mutations in JAK1 have been reported in acute lymphoblastic leukemias, but little is known about the mechanisms involved in their constitutive activation. Here, we studied the ability of JAK1 V658F and A634D to activate the Janus kinase (JAK)/STAT pathway upon ectopic expression in HEK293 cells alone or together with the other components of the interleukin-9 receptor complex (IL-9Rα, γc, and JAK3). Expression of JAK1 mutants alone failed to trigger STAT activation, but co-expression of the IL-9Rα chain promoted JAK1 mutant phosphorylation and STAT activation. Mutation of the FERM domain of JAK1, which is critical for cytokine receptor association, or of the single tyrosine of IL-9Rα involved in STAT recruitment abolished this activity, indicating that JAK1 mutants need to associate with a functional IL-9Rα to activate STAT factors. Several lines of evidence indicated that IL-9Rα homodimerization was involved in this process. IL-9Rα variants with mutations of the JAK-interacting BOX1 region not only failed to promote JAK1 activation but also acted as dominant negative forms reverting the effect of wild-type IL-9Rα. Coimmunoprecipitation experiments also showed the formation of IL-9Rα homodimers. Interestingly, STAT activation was partially inhibited by expression of γc, suggesting that overlapping residues are involved in IL-9Rα homodimerization and IL-9Rα/γc heterodimerization. Co-expression of wild-type JAK3 partially reverted the inhibition by γc, indicating that JAK3 cooperates with JAK1 mutants within the IL-9 receptor complex. Similar results were observed with IL-2Rβ. Taken together, our results show that IL-9Rα and IL-2Rβ homodimers efficiently mediate constitutive activation of ALL-associated JAK1 mutants.

Original languageEnglish
Pages (from-to)6773-6781
Number of pages9
JournalJournal of Biological Chemistry
Issue number11
Publication statusPublished - Mar 13 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


Dive into the research topics of 'Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor α homodimers'. Together they form a unique fingerprint.

Cite this