Scientists headed by a team at St. Jude Children’s Research Hospital have found that in individuals with the life-threatening blood disorder aplastic anemia (AA), different blood stem cells within the same person independently acquire gene mutations that allow cells to escape the immune attack. Through their study, the team, together with collaborating institutions, used state-of-the-art genomic techniques to profile 619 children and adults with AA. The study showed that for some patients, these “rescuing” stem cell clones were enough to restore blood production and provide long-term remission.

“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,” said Marcin Wlodarski, MD, PhD, St. Jude Department of Hematology. “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.”

Corresponding author Wlodarski and colleagues reported on the study, which they say includes the largest pediatric cohort of its kind reported to date, in Nature Genetics. In their paper titled “High-resolution single-cell mapping of clonal hematopoiesis and structural variation in aplastic anemia,” the team wrote, “These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.”

Aplastic anemia is a rare, life-threatening bone marrow failure (BMF) syndrome where patients are unable to make enough blood cells due to the immune system’s attack on hematopoietic stem and progenitor cells (HSPCs). The condition can progress to myelodysplastic syndrome (MDS) and leukemia.

In AA, autoreactive T cells target and destroy blood stem cells that display peptides on a specific protein on their surface. These are encoded by the human leukocyte antigen (HLA) gene. Each person inherits one copy of this gene from each parent, which can have different variations. People with aplastic anemia often carry a particular “risk” HLA allele (gene variant) that is thought to trigger the disease. As the authors noted, “While the precise mechanism underlying HSPC recognition by autoimmune T cells remains elusive, specific human leukocyte antigen (HLA) alleles are overrepresented in patients with AA compared with healthy controls, suggesting a role in aberrant immune recognition.”

Some blood stem cells evade the immune attack by acquiring changes that silence the risk HLA allele. This can happen via loss-of-function HLA mutations or through uniparental isodisomy 6p (UPD6p), where the risk allele is replaced with a non-risk allele. “HLA loss, manifesting as uniparental disomy of chromosome 6p (UPD6p) or loss-of-function (LOF) mutations in HLA, is postulated to inactivate HLA risk alleles (presumed to mediate autoantigen presentation), effectively shielding HSPCs from autoimmune attack,” the investigators noted. Two other types of escape in blood stem cells are known: paroxysmal nocturnal hemoglobinuria (PNH) or mutations in clonal hematopoiesis (CHIP) genes. However, it was unclear if all these changes arise in a single stem cell or arise independently to help the blood stem cells hide from the immune system. It was also unclear how this process of immune evasion impacted clinical outcomes and cancer risk.

“The clinical implications of clonal alterations in AA vary,” the investigators stated. “HLA loss is generally considered a nonmalignant adaptive lesion, large PNH clones require complement inhibitor therapy, and CHIP-mutant clones may be associated with MDS, thereby necessitating hematopoietic stem cell transplantation (HSCT).”

Blood stem cells give rise to all other blood cells, meaning their progeny are genetically identical, including any mutations gained over time. The relative abundance of a specific stem cell’s genetic “clones” measures the genetic diversity of these blood-making cells. Using single-cell analyses, the researchers showed that protective mutations happen independently in different blood stem cells and not sequentially within a single cell. These independent clones then repopulate the marrow without being found and killed by the immune system. “We saw that patients with blood stem cell clones that escape autoimmunity can improve their blood counts,” Wlodarski said. “We also learned that these clones do not indicate an increased risk for leukemia. On the contrary, they often indicate the possibility of long-lasting remission.”

To assess these clones, the scientists analyzed bone marrow and blood samples from 619 (256 children and 363 adults) patients with AA. “We present a high-resolution genomic landscape in AA patients using single-cell targeted DNA/protein sequencing, PacBio long-read whole-genome sequencing (WGS), and single-cell WGS,” they explained. They found that overall, 69% of patients carried 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, PhD, St. Jude Department of Hematology, then established and applied a single-cell DNA sequencing assay to simultaneously profile mutations and cell-surface proteins of 304,902 single cells from 48 samples. The study was complemented by long-read whole-genome sequencing and single-cell whole-genome sequencing.

The experiments showed that acquired mutations are just as common in children as in adults, but in pediatric patients, 65% of the CHIP mutations occurred in just three genes (BCOR, BCORL1, and ASXL1), compared with 27% in adults. Because age-related CHIP mutations are not expected to preexist in children, these mutations seem to be immune-escape events acquired in response to the autoimmune attack. “In children, where preexisting CHIP is not expected, mutations in these three genes may represent bona fide immune escape mechanisms arising in direct response to T-cell-mediated attack,” the authors stated.

To understand how these protective events arise and to count them precisely, the authors performed whole-genome sequencing on many single blood stem cells. They expected to see one to three events per individual; instead, they found a median of three per patient, and in one patient, 15 independent clones, all resulting in the loss of the risk HLA allele, showing convergent evolution to escape a strong immune attack. “Strikingly, HLA loss clones emerge independently through mutational events that converge on inactivating a single specific HLA risk allele, with up to 15 clones per patient identified using the scWGS platform … Our analyses reveal that somatic alterations in AA arise as independent clones rather than through sequential acquisition, and most patients carry multiple independent clones,” the investigators noted.

That extreme diversity pointed to an unusual, convergent evolutionary process, so the scientists reconstructed a phylogenetic “family tree” of individual blood stem cells by reading all mutations acquired throughout life in single whole genomes. This method enabled them to pinpoint each clone’s origin. “We had expected that these mutations occur right before disease onset,” Wlodarski said. “But we found some of these HLA-loss clones arose many years before clinical diagnosis.”

The team 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 could serve as a biomarker of long-lasting recovery. In addition, clones with loss of HLA risk alleles and CHIP mutations almost never co-occurred in the same cells, indicating that HLA loss provides enough of a proliferative advantage on its own that additional CHIP mutations, which can predispose to MDS, are not selected. So, they appear to act as protective events against their MDS and leukemia evolution.

“Clones with higher CD34+ expression levels measured in our scDNAseq/protein analysis, particularly those with HLA-loss alterations, demonstrated long-term fitness, multilineage contribution, and were often associated with stable blood counts and prolonged treatment-free intervals,” the team pointed out. These results challenge prior assumptions about when and how protective clones arise in aplastic anemia, and their presence can be a factor in restoring blood formation.

“Aplastic anemia shows us convergent evolution in miniature: Multiple independent mutational events arise in different cells, all leading to the same escape from autoimmunity,” Wlodarski said. “It shows the amazing nature of human hematopoiesis to cure itself from bad actors, like the autoimmune T cells, and reconstitute the bone marrow.” In their paper, the team concluded, “These findings enhance our understanding of clonal dynamics in AA and provide a foundation for future precision medicine approaches to address BMF in this life-threatening syndrome.”

The post Blood Stem Cells Evade Immune Attack in Aplastic Anemia Through Gene Mutations appeared first on GEN – Genetic Engineering and Biotechnology News.

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Tracking microbes is challenging, particularly when there are coexisting strains of the same species within metagenomic data. However, overcoming that challenge is important for inferring transmission of both pathogenic and commensal microbes.

A new tool, called TRAnsmision Clustering of Strains (TRACS), distinguishes between closely related bacterial strains. The “highly accurate algorithm” can be used for “estimating genetic distances between strains at the level of individual single nucleotide polymorphisms, which is robust to intra-species diversity within the host.”

Researchers used the TRACS tool to map the transmission of SARS-CoV-2, Streptococcus pneumoniae, and Plasmodium falciparum (the causative agent of malaria) across different populations. The tool may play an important role in infection prevention, outbreak response, and the development of treatments designed to help the human microbiome fight infection. They note that this tool can be used across microbial kingdoms to uncover strain dynamics.

“Traditionally, this has been very difficult for us to achieve, yet it is incredibly important to know, as people can carry several slightly different versions or strains of the same species at once, which makes it challenging to understand how microbes move between individuals,” notes Gerry Tonkin-Hill, PhD, group leader at the the Peter MacCallum Cancer Centre and the Peter Doherty Institute at the University of Melbourne, Australia. “Using this new technology, we can now overcome this challenge and gain a clearer picture of how microbes are shared between people. This will give us a better understanding of how microbes spread to help us prevent infection in vulnerable populations, like our cancer patients.”

This work is published in Nature Microbiology in the paper, “Strain-level transmission inference across multi-kingdom metagenomic data using TRACS.”

Being able to track the spread of pathogens using genomics has become a major tool in public health and can help inform new ways to prevent transmission. Additionally, it can help understand more about how lifestyle and environmental factors are involved in the transmission of these pathogens, and their role in the microbiome.

Currently, genomic tools used to track multiple bacterial species do not have the speed and flexibility required for routine public health monitoring and can struggle to distinguish between samples transmitted recently and those transmitted years ago. Furthermore, it can be difficult to continuously add in new samples, making real-time surveillance difficult.

The TRACS algorithm identifies and analyzes Single Nucleotide Polymorphisms (SNPs) to estimate how closely related the pathogens are, and if they are likely to have recently been transmitted. This approach allows for the continuous integration of new samples, making it an ideal tool for accurately identifying transmission networks and ruling out transmission events in ongoing public health applications.

In this new study, the team used TRACS to map pathogen transmission networks across three different populations, all of which had different genomic data. They applied it to SARS-CoV-2 data from U.K. hospitals, deep population sequencing data of Streptococcus pneumoniae and single-cell genome sequencing data from malaria patients infected with Plasmodium falciparum. They found that the tool was able to identify different pathogens in one sample and infer where these were each transmitted.

They also used TRACS to study how microbes are passed from mothers to infants and found that one beneficial bacterium, Bifidobacterium breve, persisted in infants longer than previously recognized, something that previous methods have missed.

More superficially, the authors note that “applying TRACS to gut metagenomic samples from a mother–infant cohort revealed species-specific transmission rates and identified increased the persistence of Bifidobacterium breve in infants, a finding previously missed owing to the presence of multiple strains.”

“This research could support the development of new treatments that use beneficial microbes to improve health,” notes Trevor Lawley, PhD, group leader at the Wellcome Sanger Institute. “By understanding exactly how microbes move between people and which of them are more likely to thrive in their microbiome, we could design better ways to increase helpful gut microbes and investigate whether there are ways to use these to help prevent infections, opening the door to safer healthcare environments and new microbiome-based therapies.”

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