Understanding How HSC-Intrinsic & -Extrinsic Alterations Cooperate to Cause Hematopoietic Aging
The process of aging causes functional decline of hematopoietic stem cells (HSCs) and the hematopoietic system, including reduced capacity for regeneration, increased risk of infections, and increased risk of certain forms of blood cancer. This is a significant health concern due to the increasing age of our population and incidence of these age-related conditions. No intervention therapies currently exist to extend hematopoietic healthspan with aging, largely due to a lack of understanding of the cellular and molecular alterations that cause functional hematopoietic decline. We are taking the approach of identifying cellular and molecular signatures of functional hematopoietic decline at its age of onset, with the rationale that this will point to early causes of decline and hence identify prime targets for extending hematopoietic healthspan (Young et al., J Exp Med 2016). Current work focuses on understanding how alterations in the bone marrow microenvironment at middle age, including decline in Insulin-Like Growth Factor 1 (IGF1) signaling (Young et al., bioRxiv 2020), contribute to functional hematopoietic decline. Our goal is to identify targeted, molecular- and cell type-specific therapeutic strategies to preserve regenerative capacity and immune cell function during aging.
Identifying Mechanisms of Age-Associated Clonal Hematopoiesis
Recent studies have identified age-dependent somatic mutations, including alleles with a role in cancer initiation, in a spectrum of human tissues. In the hematopoietic system, this has been termed clonal hematopoiesis (CH) and is most commonly caused by mutations in the epigenetic regulators DNMT3A, TET2, and ASXL1 within the hematopoietic stem and progenitor cell compartment. How the aging process promotes clonal selection and expansion of these mutant stem and progenitor cells is poorly understood. We are testing the hypothesis that increased inflammation observed during aging promotes expansion of DNMT3A-mutant HSCs, and that the fitness advantage of DNMT3A-mutant HSCs is provided by altered epigenetic regulation. Towards this goal, we have developed a mouse model of a recurrent mutation in DNMT3A found in human clonal hematopoiesis (Loberg et al., Leukemia 2019), and are using single-cell and bulk RNA-seq, ATAC-seq and DNA methylation profiling strategies, and in vitro and in vivo cell biology approaches.
Understanding Drivers of Transformation from Clonal Hematopoiesis to Blood Cancers
Individuals with clonal hematopoiesis of indeterminant potential (CHIP) have been suggested to have increased risk of developing hematologic malignancy. We strive to understand the cellular and molecular processes by which DNMT3A-mutant HSCs may be transformed to cause myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Currently, we are mechanistically interrogating a cooperating mutation in NPM1 which we have found to be capable of transformation of DNMT3A-mutant HSCs in a novel, sequentially inducible mouse model (Loberg et al., Leukemia 2019). Our goal is to understand requisite early events in the process of transformation from CHIP to blood cancers, moving beyond detection of presence/absence of cooperating somatic mutations, to support development of precise diagnostic and intervention strategies.
How Heritable Genetic Background Modifies Clonal Hematopoiesis and Blood Cancer Risk
While the vast majority of mouse models of clonal hematopoiesis and blood cancer focus on use of a single background strain (C57BL/6), human GWAS studies have clearly shown that features of non-malignant and malignant hematopoiesis have a genetic component. To understand the cellular and molecular basis of these genetic risk factors, model organism studies are needed. To this end, we are developing and interrogating genetically diverse mouse models in our studies of DNMT3A-mutant clonal hematopoiesis as well as models of acute myeloid leukemia (AML). Recent work from the lab has shown that genetic background modifies survival and blood cancer phenotype of the oncogenic fusion protein Mll-AF9 (Young et al., Exp Hematol 2020). The goal of this work is to identify mechanisms by which individuals may have inherently increased or decreased susceptibility to clonal hematopoiesis and blood cancers.