کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5534139 1550828 2017 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics
چکیده انگلیسی


- Abnormal activation of JAK/STAT signaling is present in many T-cell malignancies.
- Mutations of STAT3/STAT5b and JAK1/3 are common.
- JAK/STAT mutations are insufficient but augment upstream pathway signals.
- JAK kinase inhibitors may be of value in therapy of T-cell malignancies.

Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals. Functional cytokine receptors were required for pSTAT expression. Combining a JAK1/2 inhibitor with a Bcl-xL inhibitor navitoclax provided additive/synergistic activity with IL-2 dependent ATLL cell lines and in a mouse model of human IL-2 dependent ATLL. The insight that disorders of the γc/JAK/STAT system are pervasive suggests approaches including those that target gamma cytokines, their receptors or that use JAK kinase inhibitors may be of value in multicomponent therapy for T-cell malignancies.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular and Cellular Endocrinology - Volume 451, 15 August 2017, Pages 66-70
نویسندگان
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