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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung



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.


Seiten (von - bis)364-378.e9
PublikationsstatusVeröffentlicht - 13 Feb. 2024

Externe IDs

PubMed 38301651
ORCID /0000-0002-8691-8423/work/154190476
ORCID /0000-0002-7689-8617/work/154190647
ORCID /0000-0003-1526-997X/work/154192649
ORCID /0009-0001-6045-3349/work/154192763


Ziele für nachhaltige Entwicklung


  • Bone marrow mobilization, CBP/p300, G-CSF, HAT domain, HPA axis, Rubinstein-Taybi syndrome, bone marrow failure, glucocorticoids, neutropenia, neutrophils, Neutrophils/metabolism, Humans, Histone Acetyltransferases/metabolism, Histones/metabolism, Bone Marrow/metabolism, Hypothalamo-Hypophyseal System/metabolism