PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-associated condition in which a clonal, somatic mutation that is associated with myeloid malignancies is detectable in the peripheral blood at a variant allele fraction of at least 2%. Commonly mutated genes include the DNMT3A, TET2, and ASXL1 genes, all of which are present in myeloid malignancies and are commonly acquired early in the genetic ontogeny of these cancers. Individuals with CHIP do not have a hematologic malignancy or altered blood counts, but have a 10 to 50-fold increased risk of progression to hematologic malignancy, depending on the size of the clone and the specific somatic mutation. We propose to examine the biology of individual mutations and to understand cell-autonomous and cell non-autonomous mechanisms of clonal dominance. We will examine progression from CHIP to malignancy and the ongoing addiction of the malignant cells to the truncal mutations, thereby validating these mutations as therapeutic targets. We will integrate these biological studies with large-scale genetic studies to examine the risk of malignant transformation and clinical consequences of specific mutations. Finally, in the context of solid tumors, we will examine how CHIP generates tumor- infiltrating macrophages with aberrant function, and how these somatically mutated macrophages influence solid tumor biology, immune response, and response to immunotherapy.