RNA splicing factor Rbm25 underlies heterogeneous preleukemic clonal expansion in mice.
Publication Year:
2023
PubMed ID:
36947858
Funding Grants:
Public Summary:
Cancer often begins with the expansion of a group of cells with genetic mutations. While some of these mutations can be linked to cancer, they are also found in healthy individuals. In a study using a mouse model, researchers examined the early stages of leukemia by deleting a gene called Tet2, which is associated with leukemia. They discovered that only a small portion of hematopoietic stem cells (HSCs), responsible for blood cell production, expanded excessively when Tet2 was deleted. Surprisingly, these overexpanded HSCs had lower levels of genes associated with leukemia and RNA splicing compared to non-overexpanded HSCs. Further experiments showed that reducing the levels of an RNA splicing factor called Rbm25 accelerated the expansion of Tet2-deleted hematopoietic cells. The findings suggest that mutations in the Tet2 gene lead to variations in the expression of an RNA splicing factor, Rbm25, which in turn drives diverse early-stage clonal expansion in preleukemic cells. This diversity may help explain why cancer risks differ among individuals.
Scientific Abstract:
Clonal expansion sets the stage for cancer genesis by allowing for the accumulation of molecular alterations. Although genetic mutations such as Tet2 that induce clonal expansion and malignancy have been identified, these mutations are also frequently found in healthy individuals. Here, we tracked preleukemic clonal expansion using genetic barcoding in an inducible Tet2 knockout mouse model and found that only a small fraction of hematopoietic stem cells (HSCs) expanded excessively upon Tet2 knockout. These overexpanded HSCs expressed significantly lower levels of genes associated with leukemia and RNA splicing than nonoverexpanded Tet2 knockout HSCs. Knocking down Rbm25, an identified RNA splicing factor, accelerated the expansion of Tet2-knockout hematopoietic cells in vitro and in vivo. Our data suggest that mutations of an epigenetic factor Tet2 induce variability in the expression of an RNA splicing factor Rbm25, which subsequently drives heterogeneous preleukemic clonal expansion. This heterogeneous clonal expansion could contribute to the variable disease risks across individuals.