By Binod Dhakal, MD, MS
“Aging is not lost youth but a new stage of opportunity and strength.” — Betty Friedan (1921-2006)
Blood cells originate from hematopoietic stem cells (HSCs). Adult HSCs are maintained in a quiescent state, a state necessary for preserving the self-renewal of stem cells and a critical factor in protecting them from premature exhaustion and toxic insults. Ensuring genomic safety and stability, mutations occurring in HSCs are mostly innocuous; however, some mutations can result in the expansion of HSC clones, harboring specific, disruptive, and recurrent genetic variants. This condition known as clonal hematopoiesis (CH) or in the past, as “age-related clonal hematopoiesis” (ARCH) was first described in the 1980s using the blood cells from a large cohort of South African women and their daughters. Since that time, we have come to understand that CH is not just associated with chronological aging, but also with several other age-related pathological conditions, including inflammation, vascular disease, cancer mortality, and high risk of hematologic malignancies.
Yesterday in the fifth plenary abstract presentation, Jennifer Myers SanMiguel, PhD, of The Jackson Laboratory, presented a novel mechanism of cell-extrinsic stressors emerging from the aging bone marrow (BM) microenvironment in promoting Dnmt3a-mutant CH. “Each stem cell accumulates somatic mutations over the years, and most of them are not relevant. However, some of the protein-coding mutations can be deleterious,” noted abstract introducer Margaret Goodell, PhD, of Texas Children’s Cancer and Hematology Centers. Self-renewal of somatic stem cells such as HSCs seems to have a limit, as serial transplantation invariably results in loss of repopulation ability. However, several studies have established that loss of Dnmt3a removes all inherent HSCs self-renewal limits and replicative lifespan, allowing indefinite HSCs propagation in vivo. A lack of in vivo models has hampered knowledge of the mechanisms driving evolution from CH to overt malignancy, and the work done by this group demonstrated that NPM1 mutation drives evolution of Dnmt3a-mutant CH to acute myeloid leukemia, and the rate of disease progression is accelerated with longer latency of CH.
In this study, Dr. SanMiguel and the group per- formed several elegant experiments to understand the role of HSC-extrinsic stressors on overcoming the impaired differentiation of Dnmt3a-mutant HSCs. Using BM from young Dnmt3aR878H/+ mice into young and old congenic recipient mice, there was an accelerated expansion of phenotypically defined Dnmt3aR878H/+ short-term HSCs and their progeny. The authors then re-isolated the Dnmt3aR878H/+ long-term HSCs from both young and aged mice and found upregulated gene signatures associated with pro-myeloid differentiation on global transcriptome analysis from the aged BM microenvironment.
In the nifty experimental model system, the authors used RNA-seq data and identified elevated levels of TNF-α and macrophage colony-stimulating factor in the aged BM microenvironment. Using an ex vivo culture system, these two cytokines overcame the differentiation block in Dnmt3a R878H/+ long-term HSCs and favored the expansion toward the pro- myeloid phenotype. Furthermore, blocking these cytokines using an agent like etanercept reversed the CH expansion in these preclinical models.
As with all good preclinical studies addressing important knowledge gaps, the results raise the question of whether the findings translate to human disease. Notwithstanding, the authors should be commended for designing the spiffy experiments needed to understand the aging-associated stressors in the BM microenvironment to propagate the CH, and potentially paving the way for molecularly targeting these cytokines to prevent CH expansion and several related consequences.
Dr. Dhakal indicated no relevant conflicts of interest.