3182 - Npm1ca Overcomes the Differentiation Block of DNMT3A-Mutant LT-HSCs to Transition MDS to Myeloproliferative Disorder

Abstract

The clinical significance of aging-associated clonal hematopoietic expansion remains a barrier to predicting risk of hematopoietic malignancy in personalized medicine. DNA methyltransferase 3A (DNMT3A) mutation is a common event in aging clonal hematopoiesis, and DNMT3A and nucleophosmin 1 (NPM1) mutations frequently co-occur in human myeloid malignancies. The mechanisms by which DNMT3A and NPM1 mutations cooperate, and whether they are sufficient to cause myeloid malignancy, are unclear. Here, using an inducible mouse model replicating the most common DNMT3A mutation found in human clonal hematopoiesis and AML (mouse Dnmt3aR878H/+), we observe an expansion and differentiation block acting at the level of long-term hematopoietic stem cells (LT-HSCs) that is accelerated when these cells are placed into an aged BM microenvironment. This differentiation block progresses to myelodysplastic syndrome (MDS) upon transplantation stress. Combining this model with a novel inducible mouse model replicating the most common NPM1 mutation found in human AML (mouse Npm1cA/+), we observe that Npm1 mutation is sufficient to overcome the impaired differentiation of Dnmt3a-mutant LT-HSCs and drives the transition from BM failure to myeloproliferative disorder (MPD) stemming from granulocyte-macrophage progenitors (GMPs). Together, our data reveal that the hematopoietic cell extrinsic BM microenvironment plays a significant role in the development of Dnmt3a-mutant clonal hematopoiesis and supports a model in which Dnmt3a mutation preceeds acquisition of Npm1 mutation in the life history of myeloproliferative disorders. Furthermore, Dnmt3a-mutant clonal hematopoiesis versus Dnmt3a- and Npm1-mutant MPD derive from distinct cell populations within the hematopoietic stem and progenitor cell compartment. Importantly, this data will be informative in the development of cell context-specific interventions to prevent progression from clonal hematopoiesis to BM failure to myeloproliferative disorders.