Research Reveals How Some Aplastic Anemia Patients Recover Bone Marrow Function

Aplastic anemia is a rare, life-threatening blood disorder caused by an autoreactive immune attack on blood stem cells, leading to failure of blood production. The condition can progress to myelodysplastic syndrome (MDS) and leukemia, yet some patients experience long-term remission. Why recovery occurs has been unclear. New findings demonstrate that immune‑evasive blood stem cell clones can repopulate marrow and restore blood formation.

St. Jude Children’s Research Hospital (Memphis, TN, USA), working with multiple collaborating institutions, profiled children and adults with aplastic anemia using high‑resolution genomic techniques. The investigators showed that independent blood stem cell clones within the same individual acquire immune‑escape changes, frequently by silencing a risk human leukocyte antigen (HLA) allele. In some patients, such “rescuing” clones restored blood production and were associated with long‑term remission.

The team detailed several escape routes. Silencing of the risk HLA allele occurred through loss‑of‑function HLA mutations or uniparental isodisomy 6p (UPD6p), which replaces the risk allele with a non‑risk allele. Additional immune‑evasion mechanisms included paroxysmal nocturnal hemoglobinuria (PNH) and mutations in clonal hematopoiesis (CHIP) genes. Using single‑cell analyses, the researchers confirmed that these changes arose independently in different stem cells rather than sequentially within one clone.

Bone marrow and blood samples from 619 patients (256 children and 363 adults) were analyzed. Overall, 69% carried at least one acquired change: HLA mutations or UPD6p in 16%, PNH clones in 44%, and CHIP mutations in 21%. A single‑cell DNA sequencing assay simultaneously profiled mutations and cell‑surface proteins across 304,902 cells from 48 samples, complemented by long‑read whole‑genome sequencing and single‑cell whole‑genome sequencing.

Acquired mutations were as common in children as in adults, but 65% of pediatric CHIP mutations occurred in BCOR, BCORL1, or ASXL1, compared with 27% in adults. Single‑cell whole‑genome sequencing revealed a median of three independent HLA‑loss events per patient, with one individual showing 15 separate clones, underscoring convergent evolution under immune pressure. Rescued clones displayed higher CD34 expression, suggesting CD34 enrichment could serve as a biomarker of long‑lasting recovery.

Clones with loss of HLA risk alleles and CHIP mutations rarely co‑occurred in the same cells, indicating HLA loss alone confers sufficient proliferative advantage and is not selected alongside CHIP alterations. The authors noted that some HLA‑loss clones originated years before clinical diagnosis. These results challenge prior assumptions about when and how protective clones arise and how they help restore hematopoiesis. The study was published in Nature Genetics on May 1.

“We found that each patient with aplastic anemia that escapes autoimmunity has multiple, independent genetic events in different blood stem cells that allow those cells to escape autoimmunity. Stem cells silence the risk HLA allele through several mechanisms, and our data show that these events are protective, benign events that don't cause progression to MDS or leukemia, even when the rescued clones grow and dominate the bone marrow,” said Marcin Wlodarski, M.D., Ph.D., corresponding author, St. Jude Department of Hematology.

“Aplastic anemia shows us convergent evolution in miniature: Multiple independent mutational events arise in different cells, all leading to the same escape from autoimmunity. It shows the amazing nature of human hematopoiesis to cure itself from bad actors, like the autoimmune T cells, and reconstitute the bone marrow,” said Wlodarski.

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St. Jude Children's Research Hospital