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

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

  • Immunity. 2024 Feb 13;57(2):364-378.e9. doi: 10.1016/j.immuni.2024.01.005.
Nikolai P Jaschke 1,  Dorit Breining 2,  Maura Hofmann 2,  Sophie Pählig 2,  Ulrike Baschant 2,  Reinhard Oertel 3,  Sofia Traikov 4,  Tatyana Grinenko 5,  Francesco Saettini 6,  Andrea Biondi 7,  Myrto Stylianou 8,  Henrik Bringmann 8,  Cuiling Zhang 9,  Tomomi M Yoshida 9,  Heike Weidner 2,  Wolfram C Poller 10,  Filip K Swirski 10,  Andy Göbel 2,  Lorenz C Hofbauer 2,  Martina Rauner 2,  Christoph Scheiermann 11,  Andrew Wang 9,  Tilman D Rachner 2
Affiliations

Affiliations

  • 1 Division of Endocrinology, Department of Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Department of Internal Medicine (Rheumatology, Allergy & Immunology) and Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. Electronic address: nikolai.jaschke@yale.edu.
  • 2 Division of Endocrinology, Department of Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
  • 3 Institute of Clinical Pharmacology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
  • 4 Max-Planck Institute of Molecular Cell Biology, Dresden, Germany.
  • 5 Institute of Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Tettamanti Research Center, University of Milano-Bicocca, University of Milano Bicocca, Monza, Italy.
  • 7 Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; Pediatria, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; Dipartimento di Medicina e Chirurgia, Università degli Studi Milano-Bicocca, Monza, Italy.
  • 8 Biotechnology Center (Biotec) Technische Universität Dresden, Dresden, Germany.
  • 9 Department of Internal Medicine (Rheumatology, Allergy & Immunology) and Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • 10 Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel-Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Planegg-Martinsried, Germany.
PMID: 38301651 DOI: 10.1016/j.immuni.2024.01.005
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.

Keywords

Bone marrow mobilization; CBP/p300; G-CSF; HAT domain; HPA axis; Rubinstein-Taybi syndrome; bone marrow failure; glucocorticoids; neutropenia; neutrophils.

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