Aging as a driver of leukemogenesis

Abstract

The presence of subclinical hemopoietic clones driven by leukemia-associated mutations is commonly observed in old age, but also occurs in younger people. We recently found that some leukemia-initiating mutations appear particularly able to found hemopoietic clones in advanced old age. We discuss the biological and clinical implications of these findings.

Figure 1. Model for clonal selection to overcome acquired changes in the hemopoietic microenvironment

Hemopoietic stem cells (HSCs) acquire genetic mutations over time, generating a mosaic of adult HSCs with different mutations, depicted here in different colors. If/when a significant change in the prevailing hemopoietic microenvironment develops, cells with a relative fitness advantage in the new environment (imparted on them by their individual mutation cargo) outgrow their peers. This paradigm is well-established in paroxysmal nocturnal hemoglobinuria (PNH) where loss of PIGA is thought to enable cells to evade immunological attack. We propose that an equivalent selection process operates in an aged hemopoietic niche to drive clonal expansion of HSCs with mutations in SF3B1, SRSF2 and possibly other genes. A key piece of evidence supporting equivalence between the two processes comes from the fact that in many cases multiple clones with independent mutations develop in the same individual (affecting PIGA in PNH and SF3B1/SRSF2 in age-related clonal hemopoiesis, ARCH). Both PNH and ARCH can progress to a neoplastic disorder such as MDS or AML in a proportion of cases.