Single-cell multi-omics analysis of hematopoietic stem cell DNMT3A mutations reveals selective hypomethylation causing myeloid cell hyperplasia

Clonal hematopoiesis (CH) usually refers to the proliferation of myeloid cells due to genetic mutations in hematopoietic stem cells (HPSC) and is the basis for
the pathogenesis of a variety of blood diseases.

A study co-led by researchers at Will Cornell Medical School, New York Presbyterian Hospital, the New York Genome Center, Harvard Medical School, and the Dana-Farber Cancer Institute suggests that a common spontaneous mutation in blood stem cells that is associated with a high risk of blood cancer and cardiovascular disease may contribute to the development
of these diseases by altering the gene activity program of stem cells and the blood cells they produce.

The researchers first took blood stem cell samples
from the bone marrow of patients in remission with multiple myeloma.

The DNMT3A gene encodes for methyltransferase, an enzyme that contributes in DNA methylation
.

DNMT3A mutations lead to the bias of hematopoietic stem cell products towards the myeloid, the expansion of immature myeloid progenitor cells in the megakaryocyte-red blood cell direction, and the expression of lineage and leukemia stem cell markers is dysated
.

"These findings help us understand how these mutant cells are growing beyond normal cells and pave the way for possible future interventions against these cells to prevent cancer and other clonal growth-related scenarios
.

The researchers plan to further investigate clonal growth caused by other mutations
.