Blood cells are among the most proliferative in the human body; each day, billions of red and white blood cells are replaced as a part of normal physiology. The process of generating new blood cells is termed hematopoiesis, a highly complex process that occurs in the bone marrow where hematopoietic stem cells (HPSCs) proliferate and differentiate into effector cells. As a highly proliferative lineage, these cells accumulate mutations over the lifetime of an individual. These mutations may lead to pre-leukemic conditions in which a subset of HPSC clones becomes dominant, termed clonal hematopoiesis of indeterminate potential (CHIP), which then may lead to myelodysplastic syndrome (MDS). Both conditions increase the risk of developing acute myeloid leukemia (AML). Although many genetic lesions which cause CHIP and MDS have been identified, the mechanisms by which these mutations cause clonal dominance and eventually cancer are poorly understood. Recently, the role of inflammatory signaling on the development of the HPSCs has emerged as a common thread of pathogenesis. The extent to which inflammatory effects are exerted by mutant HSPCs or mature immune cells within the bone marrow, and how inflammation contributes to clonal selection and progression from CHIP to MDS to overt malignancies remains to be determined.
This multi-institutional Endeavor team, located at three top research centers across the United States, will establish a molecular and cellular framework for characterization of pre-malignant and inflammatory hematopoiesis at single-cell and clonal resolution. The team hypothesizes that the recurrent mutations found in patients cause epigenetic modifications and splicing dysregulation that converges on inflammatory pathways in CHIP and MDS. Crucially, they posit that the mutated cells prime their own clonal selection by induction of, and response to pro-inflammatory stress. This work will allow the team to establish critical connections between mutation-associated perturbations and the resulting environmental effects and influences that may lead to clonal dominance in hematopoiesis.
To explore the effects of inflammation and clonal selection, the group will examine how the perturbation of epigenetic modifiers and splicing regulators affects the chromatin status and splicing at inflammatory and immune response genes. They will characterize the cellular dynamics of the bone marrow and peripheral blood from murine models and human patient samples carrying specific CHIP/MDS-associated mutations, and dissect cell-specific responses to inflammatory cytokines. By delineating the contributions of CHIP/MDS-associated mutations on inflammatory hematopoiesis, this Endeavor project will improve the diagnosis, monitoring, treatment, and prevention of hematologic malignancies.
Zhou X, Zhang P, Aryal S, Zhang L, Lu R. UTX loss alters therapeutic responses in KMT2A-rearranged acute myeloid leukemia. Leukemia. 2022.