Defining the role of DNA methylation modifier mutations in reshaping blood differentiation topology

Dan Landau

PhD, MD

Weill Cornell Medicine

Project Term: July 1, 2021 - June 30, 2026

Project Summary

The process of normal blood production requires blood stem cells to take on different identities through ‘differentiation’ such that they can give rise to mature blood cells such as red blood cells, platelets and immune cells. Notably, all of these specialized cells share the same underlying genome. This is akin to a computer that is able to execute a myriad of functions through the application of different software. In blood cells, the “software” equivalent is mediated through epigenetic modifications – a form of encoding which instructs cells as to the correct genes to activate to create a new cell identity. Importantly, blood cancers often have DNA mutations affecting proteins that are responsible for these epigenetic modifications. However, it remains unclear how the mutations and resulting epigenetic disruption lead to the malignant transformation. To address this central question, we will recreate DNA mutations in epigenetic modifiers in mouse models and interrogate how they disrupt the process of differentiation from blood stem cell to mature blood cell types. Specifically, we will apply novel genomics technologies that allow us to study the epigenetic information as well as the state of the cell at the single-cell resolution. This feature will enable us to study the process of differentiation at high resolution, capturing the dynamics of the process as well as its disruption with epigenetic mutations. Finally, it was recently observed that these mutations can also be observed in individuals without blood disorders and are a common phenomenon during normal aging. This provides a singular chance to examine the impact of epigenetic mutations in isolation, before additional disruptions have occurred such as in overt blood cancer. We will therefore apply innovative single-cell genomics technology to samples from individuals with such mutations in their blood cells to study how epigenetic mutations impact human blood cell growth and differentiation. Collectively, we aim to identify the mechanisms through which epigenetic mutations lead to blood disorders with the goal of identifying novel therapeutic avenues for blood cancer treatment and prevention.