MD Anderson study ties protein ‘reader’ ENL to common leukemia

Discovery suggests potential for BET inhibitor drugs as treatment for acute myeloid leukemia

Anyone who uses an employee badge to enter a building may understand how a protein called ENL opens new possibilities for treating acute myeloid leukemia (AML), a fast-growing cancer of bone marrow and blood cells and the second most common type of leukemia in children and adults.

Findings from a study at The University of Texas MD Anderson Cancer Center revealed the leukemia-boosting abilities of ENL, which contains a protein component called YEATS that “reads” histone proteins. Histone proteins make up chromatin, large clusters of DNA- and RNA-containing molecules comprising our body’s chromosomes. Just as a scanner “reads” data on an identification badge, ENL recognizes a type of histone modification known as acetylation.

Research results, which build upon a previous MD Anderson study of histone-reading proteins, are published in the March 1 online issue of Nature. The findings indicated treatment against ENL with a class of experimental drugs called bromodomain and extra-terminal (BET) inhibitors may be effective for treating AML.

“Our study showed that ENL is required for disease maintenance in AML,” said Xiaobing Shi, Ph.D., associate professor of Epigenetics and Molecular Carcinogenesis. “Depletion of ENL led to anti-leukemic effects, suppressing growth both in vivo and in vitro. Notably, disrupting ENL further sensitized leukemia cells to BET inhibitors.”

Histone modifications like acetylation serve as docking sites for reader proteins which recognize specific modifications, influencing downstream biological outcomes. While many such reader proteins have been identified for histone modifications called methylation, few are known to recognize histone acetylation.

Shi’s team employed CRISPR, a gene-editing tool, to deplete ENL and suppress cancer gene expression, which was crucial given that cancer cells often co-opt chromatin regulatory pathways.

“Targeting epigenetic readers represents a class of anti-cancer therapy that we believe holds clinical promise,” said Hong Wen, Ph.D., research assistant professor of Epigenetics and Molecular Carcinogenesis and co-first author of the paper. “Our study revealed ENL as a chromatin reader that regulates oncogenic programs, thus establishing ENL as a potential drug target for AML.”

MD Anderson study team members included Xiaolu Wang of the Department of Epigenetics and Molecular Carcinogenesis. Other participating institutions included The Rockefeller University, New York; Memorial Sloan Kettering Cancer Center, New York; Dana-Farber Cancer Institute, Boston; Tsinghua University, Beijing; Baylor College of Medicine, Houston; Icahn School of Medicine at Mount Sinai, New York; and Harvard Medical School; Boston.

The study was funded by the National Institutes of Health (P30CA016672, RO1CA204639-01, CA66996, CA140575, 1R01CA204020, R01HG007538 and R01CA193466), the Cancer Prevention Research Institute of Texas (RP160237 and RP170285), the Leukemia and Lymphoma Society (LLS-SCOR 7006-13), the Robert A. Welch Foundation (G1719), the Major State Basic Research Development Program in China (2016FA0500700 and 2015CB910503), and the Tsinghua University Initiative Research program.