Department of Cancer Biology; Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
T-cell acute lymphoblastic leukemia, T-ALL, glucocorticoid resistance, JAK/STAT
DOI of Published Version
Leukemia. 2017 May 30. doi: 10.1038/leu.2017.136. Link to article on publisher's site
Delgado-Martin C, Meyer LK, Huang BJ, Zinter MS, Nguyen JV, Smith GA, Taunton J, Winter SS, Roderick JR, Kelliher MA, Horton TM, Wood BL, Teachey DT, Hermiston ML. (2017). JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias. UMass Metabolic Network Publications. https://doi.org/10.1038/leu.2017.136. Retrieved from https://escholarship.umassmed.edu/metnet_pubs/116
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.