TY - JOUR
T1 - Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome
AU - Schwartzman, Omer
AU - Savino, Angela Maria
AU - Gombert, Michael
AU - Palmi, Chiara
AU - Cario, Gunnar
AU - Schrappe, Martin
AU - Eckert, Cornelia
AU - Stackelberg, Arend Von
AU - Huang, Jin Yan
AU - Hameiri-Grossman, Michal
AU - Avigad, Smadar
AU - Kronnie, Geertruy Te
AU - Geron, Ifat
AU - Birger, Yehudit
AU - Rein, Avigail
AU - Zarfati, Giulia
AU - Fischer, Ute
AU - Mukamel, Zohar
AU - Stanulla, Martin
AU - Biondi, Andrea
AU - Cazzaniga, Giovanni
AU - Vetere, Amedeo
AU - Wagner, Bridget K.
AU - Chen, Zhu
AU - Chen, Sai Juan
AU - Tanay, Amos
AU - Borkhardt, Arndt
AU - Izraeli, Shai
N1 - Funding Information:
These studies were funded by an Israel Science Foundation Legacy grant complemented by an Israel Science Foundation-Israel National Center for Personalized Medicine grant (to S.I.); an Israel Science Foundation joint grant with China (to S.I. and S.-J.C.); European Union European Research Area- NET TRANCALL (S.I., G. Cario, M. Stanulla, G.t.K., G. Cazzaniga, and C.E.); the Israel Cancer Research Fund (S.I.); the Waxman Foundation (S.I.); the William Lawrence and Blanche Hughes foundation (S.I.); the German Israel Foundation (S.I. and C.E.); the Israel Absorption Ministry (I.G.); the Israel Cancer Association (S.I.); Children with Cancer UK (S.I.); the Dotan Center for Hematological Malignancies in Tel Aviv University (S.I.); the Dora and Giorgio Shapiro Chair for hematological malignancies, Tel Aviv University (S.I.); Fondazione Italiana per la Ricerca Sul Cancro (A.M.S.); the German Consortium of Translational Cancer Research (A. Borkhardt). This research partially fulfils the requirements for a PhD of Tel Aviv University for O.S., A.R., and I.G.
PY - 2017/5/16
Y1 - 2017/5/16
N2 - 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.
AB - 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.
KW - Acute lymphoblastic leukemia
KW - CRLF2
KW - Down syndrome
KW - JAK-STAT signaling
KW - USP9X
UR - http://www.scopus.com/inward/record.url?scp=85019941813&partnerID=8YFLogxK
U2 - 10.1073/pnas.1702489114
DO - 10.1073/pnas.1702489114
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C2 - 28461505
AN - SCOPUS:85019941813
SN - 0027-8424
VL - 114
SP - E4030-E4039
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -
