Project Term
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Project Summary
Loss of chromosome Y (LOY) is common in acute myeloid leukemia (AML) yet the mechanistic and therapeutic roles of LOY remain largely unexplored. Using CRISPR-Cas9 genetic perturbation, I will interrogate individual genes and whole chromosome Y loss in models of pre-leukemic progenitor and human AML cells to determine necessary and sufficient contributors of LOY to phenotypes. This will enable discovery of novel treatment opportunities conferred by loss of chromosome Y.
Lay Abstract
Specific genetic factors tied to sex differences can affect cancer biology and patient outcomes. The Y chromosome is best known for determining male biological characteristics, but it also contains important genes that help regulate cell growth and repair. Loss of these chromosome Y genes could make cells more vulnerable to cancerous changes, particularly in blood cancers like acute myeloid leukemia (AML) – an aggressive cancer that occurs when the bone marrow produces too many abnormal white blood cells. Complete loss of the Y chromosome (LOY) occurs in around 1 in 10 male patients with AML, and we found it can affect over half of patients with a specific leukemia mutation called AML-ETO. However, the role of LOY in AML is poorly understood and there are no treatments that specifically target cells with LOY.
This research aims to understand how LOY contributes to leukemia, with a particular focus on AML. By pinpointing the ways that LOY affects leukemia development and progression, this research could help developed tailored treatments for patients with leukemia that have lost their Y chromosome, turning the weaknesses of LOY into new therapeutic opportunities.
To tackle this problem, we will first use advanced laboratory models we have developed with LOY in blood-forming stem cells to study what happens when chromosome Y is lost and how this affects cell behavior. This includes how LOY might affect growth, survival, and the ability to form mature blood cells. We will also introduce specific leukemia-causing genes, such as AML-ETO, into blood cells with or without LOY to examine how LOY might selectively promote the progression of certain types of leukemia. Using cutting-edge CRISPR technology, we will delete individual chromosome Y genes and combinations of genes to determine which are most important in driving cancerous behaviors.
Our second goal is to develop treatments that will kill only the cancer cells with LOY. Many genes on chromosome Y have counterparts on chromosome X which can have similar functions. When LOY occurs, cells may become unusually reliant on the chromosome X versions of these genes due to loss of the chromosome Y partner. Inhibiting these dependencies could selectively weaken or kill cells with LOY, identifying a unique weakness in LOY cancer cells.
This research will enhance our understanding of why LOY occurs in AML and lay the groundwork for new, personalized treatments aimed specifically at leukemias with LOY.
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