Childhood Cancer

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Role of PHF6 Mutations in Germline RUNX1 Deficiency Associated Hematopoietic Disorders

The Regents of the University of California San Francisco
Serine Avagyan, MD/PhD
Grant Type: 
RUNX1 Early Career Investigator Grants
Year Awarded: 
Type of Childhood Cancer: 
Leukemia, Predisposition
Project Description: 

The balanced function of blood stem cells ensures normal production of blood cells. Individuals with germline mutations in the RUNX1 gene (RUNX1-FPD), have an increased lifetime risk of developing leukemias. Leukemia is a state of imbalance of stem cells that produce genetically identical abnormal cancerous cells instead of diverse normal blood cells. For leukemias to initiate in RUNX1-FPD, additional genetic abnormalities are required. Common secondary “hits” in leukemia in RUNX1-FPD are mutations in PHF6, a factor that affects the chromatin in the cells and their normal cell function. How germline RUNX1 mutations and acquired PHF6 mutations synergize to cause leukemia is not known. My hypothesis is that PHF6 mutations introduce changes in the chromatin structure of the RUNX1 mutant blood stem cells. This chromatin changes lead to abnormal blood cell function in ways that alters the balance of normal blood cell production towards more immature cancer-like cells. I want to study the exact mechanism of how this happens and how leukemia is initiated. Understanding the early stages of leukemia will present opportunities for novel therapies to prevent progression of preleukemic states in RUNX1-FPD.

Project Goals

To test my hypothesis, I propose to use a system I developed that allows introduction of mutations in blood cells while fluorescently labeling stem cells with various colors. We called this system TWISTR, like the game of colors. During normal hematopoiesis in this system, blood cells are multicolored reflecting their baseline diversity. Our model is ideal for studying expansion an abnormal mutant cell due to PHF6 mutations, leading to an imbalance of colors and emergence of a dominant color, as happens in leukemia. I will use cutting-edge approaches to study the effect of PHF6 mutations in this dominant colored cells to dissect the mechanisms by which the abnormal blood cells transform into leukemia. This approaches include looking at the chromatin structure in the cell, and the genes that are expressed in a different way in the mutant cells compared to normal ones. The goal would be to identify groups of genes and pathways that become abnormal in the presence of both RUNX1 and PHF6 mutations that lead to leukemia. Knowing which pathways are abnormal will allow to disrupt them with drugs or genetic interventions as a way stop the process of leukemia formation.

Project Update 2022

My goal is to find out how abnormal preleukemic cells develop and what makes them different from the normal cells, as one can use this unique aspect of their abnormal biology to target them for treating them before they grow into a full leukemia. My work aims to understand the ways that abnormal blood cells with PHF6 mutations lead to leukemia in a germline syndrome called RUNX1-FPD with known predisposition to developing leukemia. My efforts in the past year were focused on introducing the mutations in phf6 in a zebrafish model of RUNX1 mutants. Although I was able to get phf6 mutations in the animals, the process was not very efficient and the mutant cells were very small, making it difficult to assess their effect. This is a main focus for the next year for improvement, in order to establish large enough mutant cell populations to isolate and study. A second approach uses mutant zebrafish animals to study combinatorial consequence of phf6 and runx1 mutations. We obtained the phf6 mutant lines from a collaborator last year and grew the animals in our animal facility and they are now ready for further studies, which will be the second major focus of the next year. Our goal is to look at the early blood stem and progenitor population in these double mutants and understand the pathways that are abnormal in them, which then could be targeted in leukemia where these two mutations are present together.

Co-funded by: 
The RUNX1 Research Program