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AMPK links energy metabolism and histone acetylation in leukemia-initiating cell

Xiangguo Shi

Xiangguo Shi

PhD

Baylor College of Medicine

Project Term: July 1, 2019 - June 30, 2022

How leukemia cell coordinates cellular energy metabolism and the epigenetic landscape is a fundamental question with significant clinical implications. We employ interdisciplinary approaches including molecular biology, genome engineering, disease modeling, and high-throughput sequencing technologies to discover new mechanisms of the role of AMPK in metabolic and epigenetic regulation in leukemia-initiating cells. This project will explore the potential of targeting AMPK to safely treat acute myeloid leukemia.

Lay Abstract

This project will explore the potential of targeting the protein AMPK to safely treat acute myeloid leukemia (AML). AML is the most common acute leukemia in adults and is one of the most lethal. Treatment outcomes remain poor, particularly for patients over 60 years of age who have a 5-year overall survival rate of only 10-20%. A primary cause of poor treatment outcomes is leukemia relapse, which can occur several months to years after initial remission. Leukemia relapse is mainly due to the existence and expansion of a small population of leukemia stem cells (LSCs) that are capable of self-renewal to generate additional leukemia cells. Improving the treatment outcomes of AML patients will require developing novel therapeutic strategies to specifically target this small population of leukemia stem cells. Leukemia cells are particularly sensitive to changes in the balance of intracellular energy levels. Disruption of this balance will impair leukemia cell growth and delay leukemia progression. Our research shows that disruption of AMPK, a key regulator of energy equilibrium, causes leukemia cell death in mice under dietary restriction conditions. Importantly, AMPK signaling is not required for normal hematopoietic cell growth and differentiation, so AMPK inhibition may provide a therapeutic window to treat leukemias without disrupting normal blood cells. We are working to gain a complete understanding of the mechanisms by which AMPK regulates leukemia stem cell fate to develop novel therapeutic options. We have further shown that AMPK loss affects expression of a large number of leukemia-associated genes, and we hypothesize that AMPK controls leukemic gene expression through regulating cellular energy status. We demonstrated that AMPK regulates gene expression through a modulation of the epigenetic make up of histones. Histones are the structural scaffold surrounding DNA, and epigenetic modifications affect the structure of histones, which in turn modulates the accessibility of genes to regulatory proteins. A major focus of my research is to understand the interplay between energy metabolism and the epigenetic regulation of gene expression. We will also assess the ability of targeting both AMPK and epigenetic regulatory proteins in leukemia models. We seek to gain a comprehensive understanding of the functional link of AMPK between cellular energy homeostasis and leukemic gene expression. Ultimately, we hope that our work will lead to improved therapeutic interventions for AML patients, particularly those who relapse from standard treatment.

Program
Career Development Program
Grant Subprogram
Special Fellow
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