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Comparative gene expression profiling of MHH-CALL4 cells subject to pharmacological JAK2 inhibitor treatment (ruxolitinib or CHZ868) or shRNA-mediated JAK2 depletion in vitro

ABSTRACT: Gene expression profiling was performed to characterise transcriptional programs associated with response to type I JAK2 inhibitor ruxolitinib, type II JAK2 inhibitor CHZ868 or shRNA-mediated JAK2 knockdown in MHH-CALL4 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102534 | GEO | 2018/05/31

REPOSITORIES: GEO

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Project description:Hemophagocytic lymphohistiocytosis (HLH) comprises an expanding array of immune system disorders in which activated T and myeloid cells overproduce pro-inflammatory cytokines, many of which signal via the JAK/STAT pathway. Towards this end, use of the JAK1/2 inhibitor ruxolitinib has shown promising results in HLH pre-clinical and early phase clinical studies. Nevertheless, there remains concern for ruxolitinib-induced cytopenias, which are postulated to result from blockade of JAK2-dependent hematopoietic growth factors. To explore whether inhibition of JAK1, while sparing JAK2, might lessen inflammation and minimize hematologic toxicities in mouse models of HLH, we carried out experiments incorporating the JAK1 inhibitor itacitinib and the JAK2 inhibitor fedratinib. Itacitinib and fedratinib were well-tolerated and suppressed in vivo IFNg-mediated STAT1 phosphorylation. JAK1 inhibition with itacitinib lessened tissue infiltration of immune cells and significantly decreased serum cytokine levels of in a model of secondary (non-familial) HLH in which mice receive repeated doses of CpG DNA and IL-10 receptor blockade. However, its effects in a model of primary (familial) HLH where perforin-deficient (Prf1–/–) mice are infected with Lymphocytic Choriomeningitis virus (LCMV) were less pronounced. JAK2 inhibition with fedratinib exerted beneficial effects in both models, where it functioned similarly to ruxolitinib in improving cytopenias and reducing splenomegaly, hypercytokinemia and T cell IFNg production. RNA sequencing revealed that itacitinib induced only modest changes in gene expression in T and myeloid cells from LCMV-infected mice, while fedratinib downregulated pathways involved in cell proliferation, metabolism and oxidative phosphorylation. Neither drug rivaled the anti-inflammatory transcriptional changes seen with ruxolitinib. In summary, itacitinib and fedratinib are tolerated in mice models of primary and secondary HLH at or above clinically-relevant doses but exert differential effects with itacitinib showing partial disease improvement in the model of secondary HLH and fedratinib showing benefits similar to ruxolitinib in primary HLH.

Dataset Information

Comparative gene expression profiling of MHH-CALL4 cells subject to pharmacological JAK2 inhibitor treatment (ruxolitinib or CHZ868) or shRNA-mediated JAK2 depletion in vitro

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