title: Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia.
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.
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors: Shannon L
authors: SL
authors: Maude
authors: Leukaemia Biology, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
authors: Sibasish
authors: S
authors: Dolai
authors: Division of Hematology/Oncology, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA;
authors: Cristina
authors: C
authors: Delgado-Martin
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
authors: Tiffaney
authors: T
authors: Vincent
authors: Leukaemia Biology, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
authors: Alissa
authors: A
authors: Robbins
authors: Leukaemia Biology, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
authors: Arthavan
authors: A
authors: Selvanathan
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
authors: Theresa
authors: T
authors: Ryan
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
authors: Junior
authors: J
authors: Hall
authors: Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand;
authors: Andrew C
authors: AC
authors: Wood
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors: Sarah K
authors: SK
authors: Tasian
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors: Stephen P
authors: SP
authors: Hunger
authors: Division of Hematology/Oncology, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA;
authors: Mignon L
authors: ML
authors: Loh
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN; and.
authors: Charles G
authors: CG
authors: Mullighan
authors: Division of Hematopathology, University of Washington and Seattle Cancer Care Alliance, Seattle, WA.
authors: Brent L
authors: BL
authors: Wood
authors: Division of Hematology/Oncology, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA;
authors: Michelle L
authors: ML
authors: Hermiston
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors: Stephan A
authors: SA
authors: Grupp
authors: Leukaemia Biology, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
authors: Richard B
authors: RB
authors: Lock
authors: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors: David T
authors: DT
authors: Teachey
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009570:Nitriles; D054504:Precursor Cells, T-Lymphoid / Q000187:drug effects / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: C000595707:BCL2 protein, human; C508605:IL7 protein, human; D015851:Interleukin-7; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; C540383:ruxolitinib; D053612:Janus Kinases
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