RECENT research has uncovered key insights into the genetic mechanisms driving age-related clonal haematopoiesis (CH), a condition linked to inflammatory cardiovascular disease and myeloid malignancies such as chronic monomyelocytic leukaemia (CMML). The study highlights the role of ASXL1, one of the most commonly mutated genes in CH, and its interaction with key proteins involved in epigenetic regulation.
ASXL1 mutations are known to promote CH, but the exact mechanisms were previously unclear. The new findings show that ASXL1 mutations impair the function of EHMT1 and EHMT2, two enzymes that modify histones in the DNA, leading to a reduction in repressive histone markers like H3K9me2 and H3K9me3. This alteration results in the derepression of transposable elements (TEs), which are normally silenced in heterochromatin, a form of tightly packed DNA.
In a mouse model of CH, aged mice with ASXL1 mutations showed notable expansion of myeloid cells in the bone marrow and significant changes in gene expression, particularly an increase in inflammatory genes and TEs. This pattern was also observed in human CMML patient samples, suggesting that ASXL1 mutations disrupt heterochromatin integrity, leading to genomic instability and disease progression.
The study suggests that targeting proteins associated with heterochromatin and TEs could provide new therapeutic avenues for treating CH, CMML, and other myeloid disorders, particularly as the global population ages.
Helena Bradbury, EMJ
Reference
Dong Z et al. A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia.
