Epigenetics of Mutation-Order-Dependent Phenotypes in Myeloid Leukemia
2020.05.05
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Plan information
Project Term: 2019-2021
Budget:About NT$3.3 million

Origin: The Tang Prize is awarded on a biennial basis, each with a cash reward of NT$40 million. Projects proposed by the laureates also receive a grant of up to NT$10 million. The 2018 grant for Biopharmaceutical Science is shared between Dr. Hunter, Dr. Druker, and Dr. Mendelsohn.

 

Project Summary: Acute Myeloid Leukemia (AML) is a deadly hematologic malignancy characterized by the accumulation of immature myeloblasts in the bone marrow and peripheral blood. The vast majority of patients are treated with cytarabine-based chemotherapy, an approach that remains unchanged for the last 40 years. For adults with AML, five year survival remains approximately 25%. New treatments guided by a deeper understanding of disease biology are therefore needed to improve this dismal survival rate.

 

Leukemia results from the stepwise accumulation of mutations over time. We found out that only when mutation of the transcription factor CEBPA occurs before signaling mutations in CSF3R is myeloid differentiation blocked and AML initiated in vivo. This is the first demonstration that mutation order is a crucial determinant of AML disease phenotype. Examination of enhancer activation revealed that wild type CEBPA binds to and activates enhancers, while mutant CEBPA prevents this activation, blocking differentiation and initiating leukemia. As enhancer activation precedes promoter activation, this finding provides a mechanistic explanation for why CEBPA mutations must occur before CSF3R mutations in AML.

 

Lysine demethylase1 (LSD1) is an enzyme that is involved in enhancer inactivation. In vitro, AMl cells are sensitive to inhibition of signaling pathways downstream of mutant CSF3R. However, both in vitro and in vivo experiments showed that the inhibition of either signaling pathways or LSD1 can’t improve survival. Excitingly, the combination of both inhibitors normalizes blood counts and doubles median survival. Thus, combination therapy represents a promising therapeutic strategy for CEBPA/CSF3R mutant AML.  

 

We hypothesize that differentiation blocking mutations produce a common epigenetic landscape that is permissive to AML development upon the acquisition of subsequent signaling mutations. Herein, we propose to expand the scope of this work to encompass additional mutational pairings, establish the mediators of this epigenetic remodeling and use this understanding to develop novel therapeutic approaches.

 

Our aims are:

1. Define the epigenetic consequences of mutation order.

2.Establish the role of LSD1 as a mediator of mutant CEBPA-dependent differentiation blockade.               

3. Enhancer reactivation as a therapeutic strategy in CBF(core binding factor)/CEBPA AML

 

Expected outcomes--This proposal seeks to understand the early biology associated with the impact of mutation order on AML biology. Through these studies we will: 1) determine whether a mutation order dependency exists for other types of leukemic fusion proteins. 2) identify enhancers impacted by CEBPA. 3) determine the contributions of LSD1 to the CEBPA-mediated differentiation blockade. 4)evaluate the effectiveness of LSD1 inhibitors using primary AML samples.