Genetic Resistance to Leukemia

Unlike genetic mutations that are inherited directly from parents, somatic mutations are changes in the DNA that occur over a singular lifetime and accumulate. All the tissues in body are created and maintained by particular stem cells or progenitor cells. When mutations occur in stem cells or progenitor cells that give a survival advantage over the unmutated variety, they can grow via clonal expansion. The mechanism(s) of such expansion (clonal hematopoiesis) have been identified; however, the factors that may contribute to delaying this cell growth is poorly understood. Uncontrolled clonal expansion in hematopoietic stem cells or progenitors may lead to leukemia.

Human Leukemic White Blood Cells

In a recent article in the journal, Science, Agarwal et al. have studied and reported on an inheritable genetic variant that seems to protect against clonal hematopoiesis and its possible progression to leukemia.

According to the investigators in this study, “The focus of clonal expansion studies, which have led to the identification of aging-associated clonal hematopoiesis of indeterminate potential (CHIP). CHIP is defined by the presence of somatic mutations in at least one gene associated with cancer in white blood cells (the most frequently mutated genes being DNA methyltransferase 3 a, or DNMT3A; tet methylcytosine dioxygenase 2, or TED; and ASXL transcriptional regulator 1, or ASXLI), with a proportion of cancer-associated variant copies of a gene (variant allele frequency) of at least 2% in blood and bone marrow cells, and in the absence of another blood disorder. Most CHIP mutations give a competitive advantage to hematopoietic stem cells (HSCs) over normal HSCs, particularly in eroded and aged hematopoietic systems exposed to inflammation (2). The size of the mutant clone population is a major predictor of poor outcomes in CHIP carriers (3). In particular, CHIP is associated with a 10- to 12-fold increased risk of developing myeloid malignancy (4), a group of blood cancers. Notably, mutant HSC populations can stagnate and even shrink in an individual over a long period of time (5). Environmentally inherited factors that prevent or slow mutant clonal expansion may explain these variations.”

The researchers involved in this study went on to further elucidate the mechanism as described above. These data are exceedingly valuable in that they may ultimately lead to an effective diagnostic tool to more accurately identify the risk factors for age-associated clonal hematopoiesis.