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Rockefeller-Led Research Reveals Key Cancer-Promoting Activity of Histone Demethylase Enzyme (JMJD1C) in Acute Myeloid Leukemia (AML), and Perhaps Other Myeloid Leukemias; Possible New Drug Target

New treatment options are badly needed for acute myeloid leukemia (AML), a relatively rare form of cancer. The malignancy begins in the bone marrow, and from there, can spread rapidly to the bloodstream, depriving the body of the essential blood cells that carry oxygen and fight infections. Now, new work from a team led by Rockefeller University researchers in New York City has revealed a potential genetic weakness of this leukemia, offering insights into the molecular mechanisms behind AML, and suggesting a new target for drug development. Previously, researchers had identified a variety of mutations associated with this disease, including a DNA rearrangement found in approximately 15 percent of patients. The abnormal DNA-binding protein produced as a result of this rearrangement takes on entirely new functions, dramatically altering a set of genes that are turned on in a cell to promote the cancer. But how this mutation effects these changes has remained a mystery. In their new work published in the October 15, 2015 issue of Genes and Development, the researchers describe how they identified the molecular mechanism responsible for this gene activation. Their article is titled “JMJD1C Is Required for the Survival of Acute Myeloid Leukemia by Functioning As a Coactivator for Key Transcription Factors.” The research team, led by Dr. Robert G. Roeder, Arnold and Mabel Beckman Professor and Head of Rockefeller's Laboratory of Biochemistry and Molecular Biology, began by searching for proteins that interact with the mutant protein, known as AE (AML/ETO) fusion protein, which is produced by the DNA rearrangement. Their screen identified JMJD1C, an enzyme that removes chemical tags, known as methyl groups, from histones, which are proteins contained in chromosomes. These tags serve as repressive marks, indicating that genes in the associated region should be turned off. To investigate the relationship between JMJD1C and AE, the team first explored the broader effects of removing JMJD1C.

"We found that numerous genes were down-regulated upon loss of JMJD1C, and the set overlaps significantly with the genes that are normally activated by AE," explains first author Dr. Mo Chen, a postdoc in Dr. Roeder's lab.

The loss of gene expression turns out to have dramatic consequences for the AML disease. The research team found that AML cells are addicted to the presence of JMJD1C, and, without it, they cannot survive. "In fact, these cells were very sensitive to depletion of JMJD1C," says Dr. Chen.

"We see an increase in apoptosis, a sort of cellular suicide."

The team confirmed that JMJD1C interacts with AE, and demonstrated that the enzyme is required for AE to exert its cancer-promoting effects. But they also found that JMJD1C plays an even a broader role in AML, beyond its interaction with AE.

"We were very surprised to find that JMJD1C is required for the proliferation of other AML cell lines, which do not have AE, so we looked for other proteins that might be responsible for JMJD1C addiction," says Dr. Chen. The team found at least two other proteins that can recruit JMJD1C to target genes in diseased cells that lack AE, fueling leukemia growth.

These results suggest that JMJD1C may play a general role in promoting growth in myeloid leukemias, according to the researchers. "We are excited because this type of general phenomena is an ideal target for drug development," Dr. Roeder says.

Scientists have previously identified various small molecules that are known to inhibit this class of enzymes. "Our work will facilitate the development of selective inhibitors against JMJD1C, which is a highly promising therapeutic target for multiple types of leukemia," Dr. Roeder adds.

The image shows cancerous mouse bone marrow cells generated by the mutant protein AE, found in 15 percent of AML patients.

[Press release] [Genes & Development abstract]