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La Jolla, CA – Scientists at La Jolla Institute for Immunology (LJI) have uncovered crucial insights into how a gene mutation can lead to severe blood diseases, including leukemia. The groundbreaking study, published in the Proceedings of the National Academy of Sciences, delves into the mutation of the ASXL1 gene, offering new understanding into the mechanisms behind clonal hematopoiesis, a precursor to malignancies such as chronic monomyelocytic leukemia.
The study, led by LJI Instructor Zhen Dong, Ph.D., reveals how the mutated ASXL1 gene sets off a chain reaction during blood cell production, ultimately leading to dysfunctional cells in the bone marrow and blood. “We know that many diseases—and all cancers—are driven by mutations in the genome,” says Dr. Dong, the first author of the study. “Our findings show how a mutation in ASXL1 can cause significant disruptions in blood cell development.”
Clonal Hematopoiesis and Its Link to Cancer
The research focused on the link between mutated ASXL1 and clonal hematopoiesis, a condition commonly seen in older adults where the bone marrow produces blood cells with unstable genomes. The disease results in the production of defective blood cells, which may eventually develop into various forms of cancer. As mutated blood cells multiply uncontrollably, they replace healthy cells, increasing the risk of cancer and inflammation.
“This instability in the genome leads to the development of cells with defective DNA, which can trigger harmful inflammation and accelerate the development of diseases like cancer and cardiovascular issues,” says Dr. Dong.
In some cases, the mutated blood cells may even trigger immune responses, leading to inflammation that can damage vital organs like the heart. “The accumulation of proinflammatory immune cells exacerbates heart inflammation and can potentially accelerate heart failure,” adds Dr. Dong.
Understanding the Mechanism Behind the Mutation
While mutations in ASXL1 have long been associated with blood cancers, the exact mechanism remained unclear. In their study, the LJI team utilized mouse models to investigate how ASXL1 mutations contribute to the disease. By analyzing mice ranging from 10 months to 2 years old, the researchers sought to replicate the effects of aging, as clonal hematopoiesis typically emerges with age in humans.
Through mass spectrometry, the researchers discovered that mutated ASXL1 disrupts the normal function of heterochromatin, a form of tightly packed DNA responsible for silencing harmful genes. This disruption led to the activation of genes that are normally shut off in hematopoietic stem cells, which are responsible for producing all blood cells.
The malfunction of this process caused the hematopoietic stem cells to fail in differentiating properly into normal blood cells, such as red and white blood cells. Additionally, mutated ASXL1 interacted with a protein complex in cells, triggering a cascade of changes that led to a scrambled genome and abnormal cell behavior.
Implications for Future Research
The study’s findings open new avenues for understanding how ASXL1 mutations interact with other genetic players, including TET2, a protein often mutated in blood cancers. “We need to explore how these genes may cooperate in diseases like leukemia and myelodysplastic syndrome,” says Dr. Dong.
Further research could also illuminate the potential links between ASXL1 mutations and neurodevelopmental disorders, which may be especially relevant to children with speech delays, motor issues, and intellectual challenges.
“There’s a personal motivation for me,” says Dr. Dong, whose own son has a neurodevelopmental delay. “Understanding the full impact of the ASXL family of genes could unlock critical insights into a range of conditions.”
This work has important implications not only for blood cancers but also for potential treatments for diseases driven by gene mutations, offering hope for new therapies in the future.
Additional authors include co-first author Hugo Sepulveda, Leo Josue Arteaga Vazquez, and others, with the full study titled “A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia”, published in Proceedings of the National Academy of Sciences (2025).
For more information, the study is available at DOI: 10.1073/pnas.2413302121.
