Nonselective β-Adrenergic Receptor Inhibitors Impair Hematopoietic Regeneration in Mice and Humans after Hematopoietic Cell Transplants
Peripheral nerves promote mouse bone marrow regeneration by activating β2- and β3-adrenergic receptor signaling, raising the possibility that nonselective β-blockers could inhibit engraftment after hematopoietic cell transplants (HCT). We observed no effect of β-blockers on steady-state mouse hematopoiesis. However, mice treated with a nonselective β-blocker (carvedilol), but not a β1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received nonselective, but not β1-selective, β-blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received posttransplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, nonselective β-blockers were associated with little or no delay in engraftment. The inhibitory effect of nonselective β-blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells. Significance: Patients who receive allogeneic HCTs followed by posttransplant chemotherapy for graft-versus-host disease prophylaxis may be at risk of delayed engraftment and increased mortality if administered nonselective β-blockers after transplantation. Transient discontinuation of nonselective β-blockers or transitioning to β1-selective inhibitors after HCT may accelerate engraftment and improve clinical outcomes. See related commentary by Bhatia, p. 666.
Authors
- Fatma N. Kalkan (ORCID: https://orcid.org/0000-0002-1053-1193)
- Rahul Shah
- Aram Bidikian (ORCID: https://orcid.org/0000-0001-5856-5926)
- Stephen S. Chung (ORCID: https://orcid.org/0000-0002-1433-7419)
- Chul Ahn (ORCID: https://orcid.org/0000-0002-2997-9203)
- Wenhuo Hu (ORCID: https://orcid.org/0000-0002-8686-7160)
- Bo Shen (ORCID: https://orcid.org/0000-0002-5237-6144)
- Jinsuke Nishino (ORCID: https://orcid.org/0009-0007-9736-8678)
- Xiang Gao (ORCID: https://orcid.org/0000-0002-0943-9154)
- Adetola A. Kassim (ORCID: https://orcid.org/0000-0002-0484-5903)
- Zhiyu Zhao (ORCID: https://orcid.org/0000-0001-6308-6997)
- Ashwin Kishtagari (ORCID: https://orcid.org/0000-0003-1149-4571)
- Brian C. Shaffer (ORCID: https://orcid.org/0000-0003-3433-9179)
- Naimisha Marneni (ORCID: https://orcid.org/0009-0008-6237-9024)
- Amer Methqal Zeidan (ORCID: https://orcid.org/0000-0001-7017-8160)
- Sean J. Morrison (ORCID: https://orcid.org/0000-0003-1587-8329)
- Russell Vittrup (ORCID: https://orcid.org/0009-0005-0837-719X)
- Abeer Ahmedrabie (ORCID: https://orcid.org/0009-0004-7373-5806)
- Robert H. Collins (ORCID: https://orcid.org/0000-0003-0313-2394)
- Lohith Gowda (ORCID: https://orcid.org/0009-0001-1726-9749)
- Yazan F. Madanat (ORCID: https://orcid.org/0000-0001-9573-2690)
- Ang Gao (ORCID: https://orcid.org/0000-0001-6530-8768)
- Abhisar V. Cherukuri (ORCID: https://orcid.org/0009-0002-9849-9307)
- Caroline M. Blackman (ORCID: https://orcid.org/0009-0003-2555-3277)
Institutions
- St. Jude Children's Research Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Yale Cancer Center (US)
- Yale University (US)
- National Institute of Biological Sciences, Beijing (CN)
- Southwestern Medical Center (US)
- National Cancer Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University Medical Center (US)
- Tsinghua University (CN)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1158/2159-8290.cd-24-0719
- Citations
- 4
- Primary Topic
- Hematopoietic Stem Cell Transplantation
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- University of Texas Southwestern Medical Center
- Edward P. Evans Foundation
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- National Natural Science Foundation of China
- National Institutes of Health
- Directorate for Biological Sciences
- National Cancer Institute