通过酪氨酸非磷酸化 STAT5 和 JAK 抑制维持造血干细胞。
Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition.
发表日期：2024 Oct 07
作者：
Matthew J Williams, Xiaonan Wang, Hugo P Bastos, Gabriela Grondys-Kotarba, Qin Wu, Shucheng Jin, Carys S Johnson, Nicole Mende, Emily Francesca Calderbank, Michelle Wantoch, Hyun Jung Park, Giovanna Mantica, Rebecca Louise Hannah, Nicola K Wilson, Dean C Pask, Tina L Hamilton, Sarah J Kinston, Ryan Asby, Rachel Sneade, E Joanna Baxter, Peter J Campbell, George S Vassiliou, Elisa Laurenti, Juan Li, Berthold Gottgens, Anthony R Green
来源：
Blood Advances
摘要：
成体造血干细胞（HSC）负责终生生成血液和免疫细胞，这一过程受到包括细胞因子在内的细胞外信号的调节。许多细胞因子通过保守的 JAK/STAT 途径发出信号，其中酪氨酸磷酸化 STAT (pSTAT) 充当转录因子。 STAT5 是已知调节造血功能的多种细胞因子的关键下游介质，但其在 HSC 区室中的功能仍知之甚少。在这里，我们发现 STAT5 缺陷的 HSC 表现出一种不寻常的表型：多谱系再增殖和自我更新减少，同时退出静止状态减少和分化增加。这不仅是由于典型的 pSTAT5 信号传导的丧失，也是由于缺乏典型酪氨酸磷酸化的 STAT5 (uSTAT5) 介导的独特转录功能的丧失。与这一概念一致，不可磷酸化的 STAT5 突变体的表达限制了野生型 HSC 的分化，促进其维持并上调与静止和干性相关的转录程序。 JAK1/2 抑制剂 ruxolitinib 可增加 uSTAT5:pSTAT5 比率，对小鼠 HSC 功能具有类似的影响：它限制 HSC 分化和增殖，促进 HSC 维持并上调与干性相关的转录程序。 Ruxolitinib 还增强了正常人 HSPC、CALR 突变鼠 HSC 和从骨髓纤维化患者获得的 HSPC 的连续重新接种。因此，我们的结果揭示了 pSTAT5 和 uSTAT5 在控制 HSC 功能中以前未被认识的相互作用，并强调 JAK 抑制是在离体培养期间增强 HSC 功能的潜在策略。 uSTAT5 水平升高也可能导致 JAK 抑制剂无法根除骨髓增生性肿瘤。版权所有 © 2024 美国血液学会。
Adult haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells, a process regulated by extracellular cues including cytokines. Many cytokines signal through the conserved JAK/STAT pathway, in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate haematopoiesis but its function in the HSC compartment remains poorly understood. Here, we show that STAT5-deficient HSCs exhibit an unusual phenotype: reduced multi-lineage repopulation and self-renewal, combined with reduced exit from quiescence and increased differentiation. This was driven not only by loss of canonical pSTAT5 signalling, but also by loss of distinct transcriptional functions mediated by STAT5 lacking canonical tyrosine phosphorylation (uSTAT5). Consistent with this concept, expression of an unphosphorylatable STAT5 mutant constrained wild-type HSC differentiation, promoted their maintenance and upregulated transcriptional programs associated with quiescence and stemness. The JAK1/2 inhibitor, ruxolitinib, which increased the uSTAT5:pSTAT5 ratio, had similar effects on murine HSC function: it constrained HSC differentiation and proliferation, promoted HSC maintenance and upregulated transcriptional programs associated with stemness. Ruxolitinib also enhanced serial replating of normal human HSPCs, CALR-mutant murine HSCs and HSPCs obtained from patients with myelofibrosis. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function and highlight JAK inhibition as a potential strategy for enhancing HSC function during ex vivo culture. Increased levels of uSTAT5 may also contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.Copyright © 2024 American Society of Hematology.