Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis.,Cell Stem Cell

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Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2017-10-05 , DOI: 10.1016/j.stem.2017.08.011
Maria Kleppe ₁ , Matthew H Spitzer ₂ , Sheng Li ₃ , Corinne E Hill ₁ , Lauren Dong ₁ , Efthymia Papalexi ₁ , Sofie De Groote ₁ , Robert L Bowman ₁ , Matthew Keller ₁ , Priya Koppikar ₁ , Franck T Rapaport ₄ , Julie Teruya-Feldstein ₅ , Jorge Gandara ₆ , Christopher E Mason ₆ , Garry P Nolan ₇ , Ross L Levine ₈

Affiliation

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Program in Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Neurological Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Pathology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.
Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Program in Immunology, Stanford University, Stanford, CA 94305, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

JAK1 is a critical effector of pro-inflammatory cytokine signaling and plays important roles in immune function, while abnormal JAK1 activity has been linked to immunological and neoplastic diseases. Specific functions of JAK1 in the context of hematopoiesis, and specifically within hematopoietic stem cells (HSCs), have not clearly been delineated. Here, we show that conditional Jak1 loss in HSCs reduces their self-renewal and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient HSCs exhibit decreased competitiveness in vivo and are unable to rescue hematopoiesis in the setting of myelosuppression. They exhibit increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and a marked reduction in cytokine sensing, including in response to type I interferons and IL-3. Moreover, Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Together, these data highlight an essential role for Jak1 in HSC homeostasis and stress responses.

中文翻译：

Jak1 整合细胞因子感应来调节造血干细胞功能和应激造血。

JAK1 是促炎细胞因子信号转导的关键效应子，在免疫功能中发挥重要作用，而异常的 JAK1 活性与免疫和肿瘤疾病有关。 JAK1 在造血过程中，特别是在造血干细胞 (HSC) 中的具体功能尚未明确描述。在这里，我们发现 HSC 中条件性 Jak1 缺失会降低其自我更新并显着改变体内淋巴/骨髓分化。 Jak1缺陷的HSC在体内表现出竞争力下降，并且无法在骨髓抑制的情况下挽救造血功能。它们表现出更多的静止状态，无法进入细胞周期来响应造血应激，并且细胞因子感应显着减少，包括响应 I 型干扰素和 IL-3。此外，Jak1 缺失并不能通过表达组成型活性 Jak2 等位基因来完全挽救。总之，这些数据强调了 Jak1 在 HSC 稳态和应激反应中的重要作用。

更新日期：2017-09-29

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