Gene switch offers target for leukemia therapy, study finds
Scott Armstrong, MD, PhD, a lead author of the Cancer Cell paper.
Like an oaf who wanders onto the set of an elaborate Hollywood dance number, the gene MLL is often found out of sync, out of position, or paired with the wrong gene in leukemia cells. Efforts to study this bone marrow cancer by creating mice whose MLL and AF4 genes are fused together – as occurs in many human cases of acute lymphoblastic leukemia (ALL) – have been beset with technical problems.
In a study recently published in Cancer Cell, researchers at Dana-Farber reported success in developing such mice, an advance that points to a particular gene switch as spurring the cancer cells' growth and as a prime target for future ALL therapies.
Previous studies suggested that "fusion" proteins such as the one produced by the MLL-AF4 combo rev up both gene activity and cell proliferation by ordering an increase in an enzyme called methyltransferase DOTL1. This enzyme orchestrates a process called histone methylation, in which compounds of carbon and hydrogen known as methyl groups are attached to the proteins around which DNA is wrapped, raising or lowering the activity of certain genes depending on the groups' placement.
Andrew Kung MD, PhD, also a lead author of the study.
In the Cancer Cell study, researchers led by Dana-Farber's Scott Armstrong, MD, PhD, and Andrew Kung MD, PhD, focused on a methyl group known as histone 3 lysine 79 (or H3K79). Using a technique known as ChIP-chip analysis, they showed that H3K79 methylation is increased in both mouse and human leukemia cells containing the MLL-AF4 tandem, and that this elevation is associated with heightened gene activity, or expression. When they suppressed H3K79 methylation, gene expression dropped.
"Our results demonstrate that H3K79 methylation is a distinguishing feature of mouse and human ALLs in which MLL and AF4 have fused, and that it plays a key role in gene activity in these cancer cells," Armstrong states. "DOTL1's role in methylation makes it an inviting target for therapies aimed at reducing this type of methylation and the growth of ALL cells with MLL rearrangements."
Contributors to the paper include Andrei Krivtsov, PhD, Zhaohui Feng, Madeleine Lemieux, PhD, Jonathan Jesneck, PhD, and Xiaobo Xia, PhD, Sridhar Vempati, PhD, Amit Sinha, PhD, and Lewis Silverman, MD, of Dana-Farber and Children's Hospital Boston, and colleagues at Brigham and Women's Hospital, and Trinity College, Dublin, Ireland.
— Rob Levy
Robert_Levy@dfci.harvard.edu
