1. JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias.
- Author
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Delgado-Martin C, Meyer LK, Huang BJ, Shimano KA, Zinter MS, Nguyen JV, Smith GA, Taunton J, Winter SS, Roderick JR, Kelliher MA, Horton TM, Wood BL, Teachey DT, and Hermiston ML
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Bcl-2-Like Protein 11 metabolism, Cell Line, Tumor, Dexamethasone pharmacology, Disease Models, Animal, Humans, Janus Kinase Inhibitors pharmacology, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Proto-Oncogene Proteins c-bcl-2 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm, Glucocorticoids pharmacology, Interleukin-7 metabolism, Janus Kinases metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, STAT Transcription Factors metabolism, Signal Transduction drug effects
- Abstract
While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 (IL7) stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.
- Published
- 2017
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