Preventing and Understanding CHIP Evolution into AML: The role of the LY75 in the development of DNMT3A-mutant CH and associated myeloid neoplasms

Myeloid neoplasms (MN) affect ~10 per 100,000 individuals per year and remain lethal to the majority. Most cases of MN arise from the clonal expansion of an HSC and its progeny driven by MN-associated somatic mutations; a condition known as Clonal Hematopoiesis (CH) and develop many decades after the initial mutational event. DNMT3A is one of the most frequently mutated genes in CH, and its mutations have been identified in ~30% of patients with de novo AML. The Lymphocytic Antigen 75 (LY75) gene was identified as a novel locus implicated in CH-driven AML and encodes a macrophage mannose receptor of C-type lectin. Two missense coding polymorphisms (rs78446341 (P1247L) and rs147820690 (G525E)) in LY75 were associated with reduced incidence of DNMT3A-CH. Here, we will investigate the role of LY75 in DNMT3A-CH to develop approaches that inhibit clonal expansion and, by extension, stop progression to AML and other MNs. We will study hematopoietic-specific function of LY75 and the consequences of the two missense variants on the bone marrow hematopoietic and stromal cells compartments, including at the single cell level, to determine their impact on cellular abundance, differentiation trajectories and cell fate decisions, whilst linking these to changes in gene expression. Moreover, we will study the impact of these polymorphisms on the LY75 protein structure, to explore how they affect protein function potentially by altering binding of the ligand, and how these changes may be associated with reduced incidence of Clonal Hematopoiesis of Indeterminate Potential (CHIP). The implementation of the PAUSE-AML project will bring transformative change in myeloid cancer management, by shifting the emphasis from treatment towards prevention to delay disease onset, by understanding the linked processes of clonal expansion and leukemic progression and by defining potential therapeutic approaches.