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

• DOI: 10.1016/j.immuni.2024.01.005
• Publication Date: 2024-01-31T14:29:41Z
• Authors: Nikolai P. Jaschke; Dorit Breining; Maura Hofmann; Sophie Pählig; 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 Göbel; Lorenz C. Hofbauer; Martina Rauner; Christoph Scheier...; Andrew Wang; Tilman D. Rachner
• Keywords: Histone acetyltransferase; Leukopenia

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