Journal
BLOOD
Volume 125, Issue 11, Pages 1759-1767Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-06-580480
Keywords
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Categories
Funding
- National Institutes of Health, National Cancer Institute [CA102646, CA1116660, R56A1099301, K08CA184418]
- Leukemia and Lymphoma Society, Patient Impact Initiative
- Larry and Helen Hoag Foundation Clinical Translational Research Career Development Award
- American Cancer Society [RSG-14-022-01-CDD, RSG0507101]
- Children's Hospital of Philadelphia
- St. Baldrick's Foundation
- When Everyone Survives Foundation
- Campani Foundation
- Pepp Family Foundation
- Alex's Lemonade Stand Foundation
- Institute for Translational Medicine and Therapeutics at the University of Pennsylvania
- Australian National Health and Medical Research Council
- [U10 CA98543]
- [U10 CA98413]
- [U24 CA114766]
- [UL1RR024134]
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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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