2015
DOI: 10.1016/j.ccell.2015.06.005
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Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia

Abstract: Summary A variety of cancers depend on JAK2 signaling, including the high-risk subset of B-cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 … Show more

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Cited by 106 publications
(95 citation statements)
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“…However, pharmacological JAK2 inhibition using type I JAK2i ruxolitinib or genetic depletion or deletion of JAK2 resulted in only a marginal decrease in cell proliferation with little or no induction of cell death. Treatment of these leukemias with CHZ868 resulted in apoptosis (Wu et al 2015); however, we demonstrate that this compound remained potent even in JAK2-depleted CRLF2/JAK2 mutant B-ALLs, indicating a putative off-target effector mechanism. Consequent interrogation for mechanisms underlying the maintenance of proliferation of CRLF2/mutant JAK2-driven B-ALLs following sustained genetic or pharmacological targeting of JAK2 revealed enhanced c-Myc protein expression and a compensatory c-Myc-driven gene expression signature that may have mediated prolonged growth of these cells.…”
mentioning
confidence: 59%
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“…However, pharmacological JAK2 inhibition using type I JAK2i ruxolitinib or genetic depletion or deletion of JAK2 resulted in only a marginal decrease in cell proliferation with little or no induction of cell death. Treatment of these leukemias with CHZ868 resulted in apoptosis (Wu et al 2015); however, we demonstrate that this compound remained potent even in JAK2-depleted CRLF2/JAK2 mutant B-ALLs, indicating a putative off-target effector mechanism. Consequent interrogation for mechanisms underlying the maintenance of proliferation of CRLF2/mutant JAK2-driven B-ALLs following sustained genetic or pharmacological targeting of JAK2 revealed enhanced c-Myc protein expression and a compensatory c-Myc-driven gene expression signature that may have mediated prolonged growth of these cells.…”
mentioning
confidence: 59%
“…S1A, B; Geron et al 2008;Wernig et al 2008), TEL-JAK2-driven T-cell ALLs (T-ALLs) (Waibel et al 2013), JAK2-amplified classical Hodgkin lymphomas (cHLs), and primary mediastinal large B-cell lymphomas (Hao et al 2014). However, these agents had limited activity against mutant JAK2-expressing B-ALL cells, putatively due to paradoxical JAK2 Y1007/1008 hyperphosphorylation mediated by these agents in these cells (Weigert et al 2012;Wu et al 2015). We noted that while ruxolitinib treatment of JAK2 I682F -expressing MHH-CALL4 B-ALL cells did cause JAK2 Y1007/1008 hyperphosphorylation (Supplemental Fig.…”
Section: Pharmacological Inhibition or Genetic Depletion Of Jak2 In Mmentioning
confidence: 99%
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“…42 Constitutive or ligand-dependent activation of JAK/STAT signaling occurs in a large fraction of patients with Ph-like ALL (CRLF2 overexpression, JAK2/EPOR rearrangements, IL7R mutations). 7,16,40 Preclinical data indicate antileukemia efficacy of JAK2 inhibitors such as ruxolitinib or novel type II JAK2 kinase inhibitors in the in vivo patient-derived xenograft models or genetically engineered mouse models, 7,19,43 and combination of ruxolitinib and standard chemotherapy will be tested in ongoing or planned clinical trials. 23 Patients with ABL1, ABL2, and PDGFRB rearrangements could be targeted by ABLtype kinase inhibitors such as dasatinib.…”
mentioning
confidence: 99%