德国德累斯顿工业大学Tilman D. Rachner团队发现，小分子CBP/p300组蛋白乙酰转移酶(HAT)抑制通过内分泌应激反应从骨髓调动白细胞。这一研究成果于2024年1月31日发表在国际顶尖学术期刊《免疫》上。

他们研究了小分子A485对该结构域的可逆抑制的影响。他们发现，A485触发急性和短暂动员白细胞从骨髓进入血液。A485对白细胞的动员与粒细胞集落刺激因子(G-CSF)同样有效，但在机制上不同，当两种化合物联合使用时，G-CSF允许添加性中性粒细胞动员。这些作用在白细胞减少模型中得以维持，并增强了宿主的防御能力。

在机制上，A485激活下丘脑-垂体-肾上腺(HPA)轴通过促肾上腺皮质激素释放激素受体1 (CRHR1)，和促肾上腺皮质激素(ACTH)传递白细胞分布的变化，但不依赖于糖皮质激素。他们的研究结果确定了一种通过神经内分泌回路快速扩张血液白细胞室的策略，这对人类病理的治疗具有重要意义。

研究人员表示，CBP/p300 HAT结构域的突变可能与人类白血病转化有关，提示白细胞室大小的检查点。

附：英文原文

Title: Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response

Author: Nikolai P. Jaschke, Dorit Breining, Maura Hofmann, Sophie Phlig, Ulrike Baschant, Reinhard Oertel, Sofia Traikov, Tatyana Grinenko, Francesco Saettini, Andrea Biondi, Myrto Stylianou, Henrik Bringmann, Cuiling Zhang, Tomomi M. Yoshida, Heike Weidner, Wolfram C. Poller, Filip K. Swirski, Andy Gbel, Lorenz C. Hofbauer, Martina Rauner, Christoph Scheiermann, Andrew Wang, Tilman D. Rachner

Issue&Volume: 2024-01-31

Abstract: Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes. Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood. Leukocyte mobilization by A485 was equally potent as, but mechanistically distinct from, granulocyte colony-stimulating factor (G-CSF), which allowed for additive neutrophil mobilization when both compounds were combined. These effects were maintained in models of leukopenia and conferred augmented host defenses. Mechanistically, activation of the hypothalamus-pituitary-adrenal gland (HPA) axis by A485 relayed shifts in leukocyte distribution through corticotropin-releasing hormone receptor 1 (CRHR1) and adrenocorticotropic hormone (ACTH), but independently of glucocorticoids. Our findings identify a strategy for rapid expansion of the blood leukocyte compartment via a neuroendocrine loop, with implications for the treatment of human pathologies.

DOI: 10.1016/j.immuni.2024.01.005

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00030-X