Clonal hematopoiesis (CH) refers to pre-malignant hematopoietic stem cells (HSCs) with fitness advantages in respect to the entire HSC population. Age-associated mutations in DNA-damage regulators and in epigenetic modifiers, specifically DNA methyltransferase 3A (DNMT3A), are primarily associated with CH along with related malignant conditions like myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While mutations in DNMT3A are commonly observed in the above conditions, a specific point mutation, an arginine-to-histidine substitution at amino acid position 882, or DNMT3AR882H, is notably more prevalent in AML patients than in those with CH in contrast to the loss-of-function mutations also observed in DNMT3A. The focus of this research is to understand the role of DNMT3AR882H in driving CH as a pre-malignant condition of AML. We propose that the point mutation will stimulate some attributes of CH yet fail to reach the levels of proliferation observed in the DNMT3A loss-of-function setting. Rosa26R-Confetti (Brainbow 2.1) multi-color reporter mice driven by a HSC-specific tamoxifen-inducible Cre (Scl-CreERT2) will be combined with conditional Dnmt3a knock-out (modeling a loss-of-function) and Dnmt3aR878H knock-in (corresponding to human R882H point mutation) lines to model the clonal development of the HSCs and subsequent myeloid dominance. By using a stochastically fluorescent model, individual HSC populations are identifiable and monitorable by their contribution to mature peripheral blood over the course of the experiment.