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      Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia.

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          Abstract

          Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile, as well as a high rate of induction failure. Frequent mutations in cytokine receptor and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to interleukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pretreatment levels and compared with control (P < .01) in 5 of 6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P < .01) in 6 of 6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed.

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          Author and article information

          Journal
          Blood
          Blood
          1528-0020
          0006-4971
          Mar 12 2015
          : 125
          : 11
          Affiliations
          [1 ] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
          [2 ] Leukaemia Biology, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
          [3 ] Division of Hematology/Oncology, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA;
          [4 ] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
          [5 ] Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand;
          [6 ] Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN; and.
          [7 ] Division of Hematopathology, University of Washington and Seattle Cancer Care Alliance, Seattle, WA.
          Article
          blood-2014-06-580480
          10.1182/blood-2014-06-580480
          4357583
          25645356
          9fd5ff8c-4bba-4874-915d-ae7609d54dbd
          © 2015 by The American Society of Hematology.

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