JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation.

Blood
Lauren K MeyerKim E Nichols

Abstract

Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate th...Continue Reading

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Citations

Aug 8, 2020·Blood·Randy Q Cron
Oct 9, 2020·Pediatric Blood & Cancer·Kenneth L McClain
Dec 19, 2020·British Journal of Haematology·Thomas A Fox, Claire Booth
Jan 7, 2021·Pediatric Blood & Cancer·Stephan EhlKim E Nichols
Dec 23, 2020·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Min LiHuabin Li
Jan 24, 2021·Pediatric Blood & Cancer·Pietro MerliFranco Locatelli
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Feb 2, 2021·European Journal of Haematology·Sarah HansenLuke Y C Chen
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Jul 20, 2021·Technology in Cancer Research & Treatment·Wenwen TangLinjiang Song
Jul 5, 2021·Trends in Immunology·Rajendra Karki, Thirumala-Devi Kanneganti

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