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The Cebpa Downstream Enhancer as a Key Target of Transformation to Acute Myeloid Leukemia

Institution: 
The Johns Hopkins University School of Medicine
Researcher(s): 
Stacy Cooper, MD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2015
Type of Childhood Cancer: 
Leukemia, Acute Myelogenous Leukemia (AML)
Project Description: 

Background

Acute myeloid leukemia (AML) accounts for 20% of pediatric leukemias, and despite considerable improvements in treatment, has an approximately 50% mortality rate. Mutations in AML can be classified into two categories: type I that stimulate proliferation, and type II that inhibit normal differentiation. C/EBPa, a protein critical for normal maturation of myeloid cells, is decreased in the majority of AML cases. Previously, the Friedman laboratory identified a DNA region encoding a C/EBPa enhancer, which functions to increase its production.

 

Project Goal:

The key hypothesis of this proposal is that reduced C/EBPa through enhancer-specific mechanisms is sufficient to cooperate with proliferative type I mutations to induce leukemia. My previous work investigated the factors that bind and regulate the enhancer, and we now propose to further characterize this area. Utilizing a mouse model that allows for enhancer deletion, we plan to monitor for development of leukemia, both alone and bred with FLT3-ITD mice, a common AML type I mutation. Additionally, to assess the interaction between the leukemia-inducing protein RUNX1-ETO and the enhancer, we plan to develop a myeloid cell line that expresses RUNX1-ETO, and assess the differences in C/EBPa levels, as well as characterize enhancer methylation as compared to controls. Finally, using a leukemia sample bank, we will analyze pediatric AML specimens for the methylation patterns in this area and the amount of C/EBPa protein produced. Results obtained will help us design novel therapies to increase C/EBPa in AML, expected to induce differentiation and so prevent their growth.