Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Omer Schwartzman, Michael Gombert, Chiara Palmi, Gunnar Cario, Martin Schrappe, Cornelia Eckert, Arend Von Stackelberg, Jin Yan Huang, Michal Hameiri-Grossman, Smadar Avigad, Geertruy Te Kronnie, Yehudit Birger, Avigail Rein, Giulia Zarfati, Ute Fischer, Zohar Mukamel, Martin Stanulla, Andrea Biondi, Giovanni Cazzaniga, Amedeo VetereBridget K. Wagner, Zhu Chen, Sai Juan Chen, Amos Tanay, Arndt Borkhardt, Shai Izraeli

Research output: Contribution to journalArticlepeer-review


Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DSALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/ RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2pos DSALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2pos, Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.

Original languageEnglish
Pages (from-to)E4030-E4039
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - 16 May 2017


  • Acute lymphoblastic leukemia
  • CRLF2
  • Down syndrome
  • JAK-STAT signaling
  • USP9X

All Science Journal Classification (ASJC) codes

  • General


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