The role of aging in promoting leukemia progression through cell-intrinsic and cell-extrinsic mechanisms

Abstract Age is the single major risk factor for numerous cancer types including leukemia. Due to population aging, it is evident that cancer incidence will continue to increase in the future. One explanation for the rapid increase in leukemias with age is the accumulation of mutations in the DNA of hematopoietic stem and progenitor cells (HSPCs) that lead to the development of leukemia stem cells. However, the accumulation of mutations is not sufficient to explain the etiology of the disease, and other factors must play a role in the increased rate of malignancies with age. We hypothesize that there are age-dependent tumor cell-intrinsic and -extrinsic factors that predispose to an increased risk of leukemia with age. To test this hypothesis, we've established a transplant model of leukemia progression in young and aged mice, without the need for potentially confounding the usual “pre-conditioning” of the recipient mice by genotoxic stress. Strikingly, aged mice exhibited a significantly shortened median survival compared to their younger counterparts. In addition, there is an accelerated progression of the leukemia cell engraftment in aged mice. Combining this model with single-cell dissociative and spatial transcriptomics technologies we have found a dysregulation of the T-cell compartment of the bone marrow during aging as a potential driver of the accelerated leukemia progression in aged mice. Aligned with the Geroscience hypothesis, a better understanding of the molecular mechanisms of aging and stem cell aging will help us better understand common diseases of the blood, including leukemias. We anticipate that this research will boost the development of new preventative interventions for age-related leukemias.