CRI scientists link hematopoietic cell transplant deaths to beta-blocker use
Morrison Lab research shows nerve signaling needed for bone marrow regeneration may be impaired by medication
DALLAS – Dec. 30, 2024 – Patients can die if they take certain previously prescribed beta-blockers during a hematopoietic cell transplant due to suppressed signals from nerves that promote bone marrow regeneration. This finding by scientists in Children’s Medical Center Research Institute at UT Southwestern (CRI), published in Cancer Discovery, builds upon previous CRI research by analyzing retrospective patient data to correlate beta-blocker use with significantly worse patient outcomes.
“This discovery has the potential to save lives by leading to changes in how hematopoietic, or blood-forming, cell transplants are managed in some patients,” said Sean J. Morrison, Ph.D., CRI Director and Professor as well as a Howard Hughes Medical Institute (HHMI) Investigator.
Hematopoietic cell transplants are commonly used to treat disorders of the blood-forming system, including some high-risk leukemias. During treatment, a patient’s blood-forming cells are wiped out with chemotherapy and radiation and replaced with transplanted hematopoietic cells.
Transplanted cells create a healthy blood-forming system by regenerating hematopoietic cells in the bone marrow. While patients have reduced blood cell counts and depleted immune cells, they are at risk of dying from infections or complications until after engraftment, when the transplanted cells have regenerated adequate blood cell counts.
Patients who receive hematopoietic cells from other donors are also at risk of graft-versus-host disease, where the donated hematopoietic cells identify a recipient’s tissues as foreign and attack them. Graft-versus-host disease is prevented with post-transplant chemotherapy to kill donor immune cells.
Morrison Lab scientists previously identified within the bone marrow the location and cellular composition of the hematopoietic stem cell niche: a specialized environment in which stem cells are maintained. They further found in 2023 that nerves promote bone marrow regeneration after irradiation or chemotherapy by activating signaling from β2 and β3 adrenergic receptors in the niche.
There are three beta-adrenergic receptors – β1, β2, and β3 – that perform numerous functions across the body, primarily to relay signals from the sympathetic nervous system to various tissues.
To block beta-adrenergic receptors, there are two classes of medication: β1-selective inhibitors and non-selective beta-blockers. Non-selective beta-blockers inhibit signaling from all three beta adrenergic receptors. Both classes of medication are taken to treat cardiovascular disease, high blood pressure, and other conditions.
Following their discovery that β2 and β3 adrenergic receptor signaling is necessary for bone marrow regeneration, Morrison Lab scientists questioned whether patients receiving a hematopoietic cell transplant, while continuing to take a beta-blocker, would engraft more slowly and have worse outcomes than patients not taking a beta-blocker.
CRI researchers hypothesized that non-selective beta-blockers, but not β1-selective inhibitors, would impair hematopoietic regeneration after transplantation, since β2 and β3 are necessary for bone marrow regeneration.
Study first author Jinsuke Nishino, M.D., Ph.D., a scientist in the Morrison Lab, first tested this hypothesis in mice. Consistent with the 2023 study, Dr. Nishino’s findings showed that beta-blockers had no effect on normal blood cell production in non-transplanted mice.
However, in transplanted mice, non-selective beta-blockers impaired hematopoietic regeneration, but β1-selective inhibitors did not. Half of the mice treated with non-selective beta-blockers died after transplantation because they couldn’t regenerate their bone marrow quickly enough.
To see whether beta-blockers affect human hematopoietic cell transplants, Dr. Morrison collaborated with Stephen Chung, M.D., Assistant Professor of Internal Medicine and in CRI and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, and Ashwin Kishtagari, Assistant Professor of Medicine at Vanderbilt University Medical Center. Both are medical oncologists who treat patients with blood cancers by performing hematopoietic cell transplants.
Drs. Chung and Kishtagari analyzed retrospective patient data from their medical centers and found that patients who received allogeneic, or unrelated donor, transplants, as well as post-transplant chemotherapy, had significantly worse outcomes if they continued taking previously prescribed non-selective beta-blockers.
“The Morrison Lab findings are relevant to patients undergoing a type of transplant used to cure leukemias and bone marrow cancers. After transplant, these patients need to be hospitalized for two to three weeks until their blood counts recover to safe levels,” Dr. Chung said. “We analyzed 10 years of data and found that patients on non-selective beta-blockers take a much longer time to recover their blood counts. We further found this led to a significantly higher rate of complications and worse survival in patients.”
Dr. Chung said reviewing another medical institution’s transplant data was important because each medical institution performs hematopoietic cell transplants slightly differently.
“Our findings could significantly alter clinical practice, though confirmation in additional patient cohorts remains essential — especially given variability in transplantation practices across institutions,” Dr. Kishtagari said. “Nonetheless, our data suggest it’s prudent that patients undergoing hematopoietic cell transplantation either discontinue non-selective beta-blockers for about three weeks or transition to a β1-selective inhibitor, if discontinuation is not feasible.”
In addition to being founding CRI Director, Dr. Morrison is Professor of Pediatrics at UT Southwestern. He holds the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern and the Mary McDermott Cook Chair in Pediatric Genetics. He is a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and a member of the Development and Cancer Research Program at Simmons Cancer Center. He recently received the E. Donnall Thomas Lecture and Prize from the American Society of Hematology for paradigm-shifting discoveries related to hematopoietic stem cells.
The research was funded by HHMI, the National Institutes of Health, the Josephine Hughes Sterling Foundation, the Kleberg Foundation, the Moody Medical Research Institute, the National Cancer Institute, the Department of Defense, and the Edward P. Evans Foundation.
About CRI
Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology and metabolism.
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About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 24 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.