Aplastic anemia is a rare, life-threatening blood disease in which the immune system attacks blood stem cells, leaving patients unable to make enough blood cells. This condition can progress to myelodysplastic syndrome (MDS) and leukemia. The study, led by scientists at St. Jude Children’s Research Hospital and in collaboration with multiple partner institutions, used cutting-edge genomic technology to profile 619 children and adults with aplastic anemia.
They discovered that different blood stem cells within the same person’s body independently acquire genetic mutations that allow the cells to escape immune attack. In some patients, these “rescued” stem cell clones were sufficient to restore blood production and result in long-term remission. This study includes the largest pediatric cohort of its kind reported to date, and today natural genetics.
In aplastic anemia, immune cells called autoreactive T cells target and destroy blood stem cells that present peptides on specific proteins on their surface. These are encoded by human leukocyte antigens (HLA) gene. Each person inherits one copy of this gene from each parent and can have different variations.
People with aplastic anemia often have certain “risks” HLA An allele (genetic mutation) that is thought to trigger a disease. Some blood stem cells evade immune attack by acquiring changes that silence the risk HLA Allele. This can occur due to loss of function HLA A mutation, or uniparental isodisomy 6p (UPD6p), causes the risk allele to be replaced by a non-risk allele.
Two other types of escape in blood stem cells are known. Paroxysmal nocturnal hemoglobinuria (PNH) or clonal hematopoiesis (CHIP) gene mutations. However, it was unclear whether all these changes occur in a single stem cell or whether they occur independently to help blood stem cells hide from the immune system. It was also unclear how this process of immune evasion affects clinical outcomes and cancer risk.
We found that each patient with aplastic anemia who escapes autoimmunity harbors multiple independent genetic events in different blood stem cells that allow those cells to escape autoimmunity. Stem cells silence risk HLA Our data indicate that these events are protective and benign and do not cause progression to MDS or leukemia, even if the rescued clone grows and dominates the bone marrow. ”
Marcin Wlodarski, MD, PhD, Department of Hematology, St. Jude Children’s Research Hospital, Lead Study Author and Associate Member
Assessing the risk of blood stem cell “cloning”
Blood stem cells give rise to all other blood cells. This means that their offspring are genetically identical, including any mutations that have occurred over time. The relative abundance of genetic “clones” of a particular stem cell measures the genetic diversity of these hematopoietic cells. Using single-cell analysis, the researchers showed that protective mutations do not occur sequentially within a single cell, but independently in different blood stem cells. These independent clones repopulate the bone marrow without being discovered and killed by the immune system.
“We found that patients with blood stem cell clones that escaped autoimmunity can improve their blood cell counts,” Wlodarsky said. “We also found that these clones did not show an increased risk of leukemia; in fact, they often showed the potential for long-term remission.”
To evaluate these clones, the scientists analyzed bone marrow and blood samples from 619 patients with aplastic anemia (256 children and 363 adults). Overall, 69% of patients had at least one acquired change. HLA Mutations or UPD6p clones were found in 16%, PNH clones in 44%, and CHIP mutations in 21%.
First author Masanori Yoshida, MD, St. Jude Hematology, subsequently established and applied a single-cell DNA sequencing assay to simultaneously profile mutations and cell surface proteins in 304,902 single cells from 48 samples. This study was complemented by long-read whole-genome sequencing and single-cell whole-genome sequencing.
Experiments showed that acquired mutations are as common in children as in adults, but in pediatric patients, 65% of CHIP mutations occurred in just three genes (BCOR, BCORL1 and ASXL1), compared to 27% in adults. Because age-related CHIP mutations are not expected to be pre-existing in children, these mutations are likely to be immune escape events acquired in response to autoimmune attack.
HLA In aplastic anemia, alleles are lost multiple times, starting early in life.
To understand how these protective events occur and accurately count them, the authors performed whole-genome sequencing on large numbers of single blood stem cells. They expected between one and three events to occur for each individual. Instead, we found that there were 15 independent clones per patient, with a median of 3 per patient, all leading to a loss of risk. HLA Alleles exhibit convergent evolution to escape strong immune attack.
Their extreme diversity indicated an unusual convergent evolutionary process, so the scientists reconstructed the phylogenetic “family tree” of individual blood stem cells by reading out all the mutations acquired over a lifetime in a single entire genome. This method allowed us to precisely identify the origin of each clone.
“We expected these mutations to occur just before the onset of the disease,” Wlodarsky said. “But we found some of these HLA-Loss clone occurred years before clinical diagnosis. ”
The researchers also showed that long-lived rescued clones had higher expression of CD34, a surface marker for blood stem and progenitor cells. This suggests that CD34 enrichment may serve as a biomarker of long-term recovery. In addition, the defective clones HLARisk alleles and CHIP mutations rarely co-occur within the same cell, indicating that HLA loss provides sufficient proliferative advantage by itself to not select for additional CHIP mutations that could predispose to MDS.
Therefore, they may function as protective events against MDS and leukemia progression. These results question previous hypotheses about when and how protective clones arise in aplastic anemia and whether their presence can be a factor in restoring blood formation.
“Aplastic anemia represents convergent evolution in miniature: multiple independent mutational events occur in different cells, all leading to the same autoimmune escape,” Brodarsky said. “This shows the amazing ability of human hematopoiesis to heal itself from bad guys like autoimmune T cells and reconstitute the bone marrow.”
sauce:
St. Jude Children’s Research Hospital
Reference magazines:
Yoshida, M., others (2026). High-resolution single-cell mapping of clonal hematopoiesis and structural changes in aplastic anemia. natural genetics. DOI: 10.1038/s41588-026-02587-x. https://www.nature.com/articles/s41588-026-02587-xx.
