Bone Marrow Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoiesis Drives Clonal Hematopoiesis and Transformation to Myeloid Malignancy
Jayna Mistry
PhDThe Jackson Laboratory
Project Term: July 1, 2023 - June 30, 2026
This project focuses on how age-associated clonal hematopoiesis (CH) alters the bone marrow (BM) microenvironment, and whether this promotes transformation of CH to acute myeloid leukemia (AML). I will utilize single cell RNA-seq data, genetic knockout models, and targeted inhibitors to perturb the non-hematopoietic and hematopoietic compartments of a mouse model of CH. The goal is to determine if manipulation of the BM microenvironment can attenuate CH and prevent AML transformation.
As we age, we acquire spontaneous mutations in our DNA. A subset of these mutations can give cells a selective advantage and can be a precursor for the development of cancer. Mutations in the gene DNMT3A are an example of this in blood and bone marrow cells. They lead to a condition called clonal hematopoiesis, and this condition increases the risk of developing blood cancers including acute myeloid leukemia (AML). We currently have a poor understanding of how DNMT3A-mutant cells outcompete non-mutated cells and how this can lead to the development of blood cancer. The specific goal of this project is to understand how DNMT3A-mutant cells change their microenvironment in the bone marrow to allow them to outcompete normal cells and eventually develop into blood cancer. Achieving this goal will allow us to identify new drugs and therapies that can intervene to slow growth of DNMT3A-mutant cells and prevent leukemia. Using a state-of-the-art mouse model of Dnmt3a-mutant clonal hematopoiesis, we have found in our preliminary studies that these mutant cells can cause accelerated aging, also known as senescence, of cells in the bone marrow microenvironment. We find that this accelerated aging in the bone marrow microenvironment promotes both clonal hematopoiesis and blood cancer growth. This discovery is unique in that it has not been previously described by other groups. The proposed project will use mouse models and cell culture assays to discover how accelerated aging of the bone marrow microenvironment causes growth of Dnmt3a-mutant cells and whether targeting senescence can slow growth of Dnmt3a-mutant cells and prevent blood cancer. This approach is unique because it uses specialized genetically engineered mouse models available at The Jackson Laboratory, a world leader in mouse genetic research. Success of this project will be indicated by identification of the mechanism(s) that promote growth of Dnmt3a-mutant cells and demonstration that targeting senescence in the microenvironment prevents progression to blood cancer. Following success of this project, the next steps will be to test these therapies in pre-clinical models using human-mouse xenograft studies. This research will benefit blood cancer patients in the future as it will discover new therapies for individuals with high-risk clonal hematopoiesis that can be given to prevent develop of blood cancer. Currently, no such therapies exist.