Senescent bone marrow support cells helped mutant blood cell clones grow; removing these cells slowed the development of malignant disease in mice
Senescent bone marrow support cells helped mutant blood cell clones grow; removing these cells slowed the development of malignant disease in mice
On August 6, Nature Cell Biology published a study of clonal hematopoiesis, a condition in which a single blood stem cell carrying a mutation produces an increasing number of descendants. The authors traced how such a clone alters the support cells in the bone marrow and tested whether this interaction could be disrupted. In experiments with mice, removing senescent cells reduced the proportion of mutant cells.
Blood stem cells reside in the bone marrow alongside stromal cells, which support blood cell production. In clonal hematopoiesis, a mutation gives one stem cell an advantage, and its descendants gradually account for an increasing share of blood cells. The growth of such clones has generally been attributed to properties of the mutant cells themselves.
In mouse models carrying a mutation in the DNMT3A gene, mutant hematopoietic cells released TNF-α and IL-6, which are signaling proteins. In stromal cells, these signals activated the STAT3 protein and increased the amount of chemically reactive oxygen species. The support cells entered senescence: they remained alive, stopped dividing, and changed the set of substances they secreted. This altered stroma gave the mutant clone an advantage over normal cells and helped it continue to grow.
To test whether this relationship was causal, the researchers removed senescent cells in three ways. They genetically eliminated cells carrying the senescence marker p16, or used one of two drug regimens: navitoclax or a combination of dasatinib and quercetin. In all three experiments, the proportion of cells carrying the DNMT3A mutation in the bone marrow decreased. In another mouse model, after such a clone had expanded, the authors activated a second mutation in the NPM1 gene, which initiated malignant transformation of hematopoietic cells. Five months later, mice that had received navitoclax during the clonal hematopoiesis stage had a lower proportion of mutant cells than mice that had not received this treatment. When the researchers transplanted their leukemia cells into another group of mice, the recipient mice lived longer.
“Clonal hematopoiesis clones can alter the bone marrow environment, creating a favorable niche that helps them gain a competitive advantage and promotes the growth of tumor cells,” the authors write.
In bone marrow samples from seven people with clonal hematopoiesis, stromal cells showed a stronger genetic signature of senescence, meaning a characteristic pattern of active genes associated with cellular aging, than stromal cells from six people without the condition. According to this model, the mutant cell gains its advantage from both its DNA and the bone marrow environment that the clone itself alters.