黑料吃瓜资源

Cold Spring Harbor, NY — Cancer researchers today announced they have developed a way of sidelining one of the most dangerous 鈥渂ad actors鈥� in leukemia. Their approach depends on throwing a molecular wrench into the gears of an important machine that sets genes into motion, enabling cancer cells to proliferate.

In tests in mice, the newly discovered method has resulted in what the researchers describe as the 鈥渕elting away鈥� of aggressive blood cancers while at the same time having no harmful impact on the function of normal cells.

The new research by Associate Professor Christopher Vakoc and colleagues at 黑料吃瓜资源 (CSHL) is part of a broader effort in Vakoc鈥檚 lab to fight the often fatal acute myeloid leukemia (AML) by disabling parts of the machinery in cells—called the transcriptional machinery—that determines when genes are switched on and off.

Central players in this machinery are proteins called transcription factors, thousands of which are active in regulating genes across our chromosomes. The question addressed in the new research, published today in Cancer Cell, was how to target one of the most troublesome transcription factors, called MYB. It鈥檚 an oncogenic, or cancer-inducing, transcription factor that enables cells to blow through the stop signs that normally prevent out-of-control growth.

鈥淢YB is a dream target in cancer research,鈥� says Vakoc, 鈥渂ecause it鈥檚 involved in so many cancers; in leukemia it鈥檚 special because we know from previous research that by targeting MYB you can get AML not just to stop growing but actually to regress.鈥� Deactivating MYB in cancer has been a goal of many research labs.

Yali Xu, a Ph.D. student in the Vakoc lab leading the study, discovered how to selectively take MYB out of the picture in leukemia by throwing a molecular wrench into the mechanism that the transcription factor normally activates. First, the team discovered that MYB activates gene expression by docking at a giant gene-鈥渃o-activation鈥� protein called TFIID (pronounced TF-two-D). Next, they found a tiny weak spot on the massive protein. This Achilles鈥� heel, called TAF12, is a small, nub-like projection. The team then tricked MYB into binding to short protein fragments, or peptides, that are shaped exactly like the place on TAF12 where MYB binds when it is promoting leukemia.

A major achievement in the study was generating this peptide, which acts like a decoy. Experiments in mice that model human AML showed that the peptide finds and binds MYB, preventing it from engaging the TFIID co-activator. This resulted in mouse leukemias shrinking in size by some 80% without causing harm to healthy cells.

While the peptide is not itself a drug, Vakoc says its action could be replicated by a drug. 鈥淚t鈥檚 a concept we鈥檙e now discussing with the pharmaceutical industry. It is going to take lots of work before it can result in a medicine leukemia patients might take. But we鈥檙e excited about this new approach, because MYB is such an important player in many cancers and until now has eluded efforts to selectively target it.鈥�

Written by: Peter Tarr, Senior Science Writer | [email protected] | 516-367-8455

Funding

黑料吃瓜资源 NCI Cancer Center Support grant; Alex鈥檚 Lemonade Stand Foundation; Forbeck Foundation; Pershing Square Sohn Cancer Research Alliance; V Foundation; Burroughs-Wellcome Fund Career Award; NIH/NCI; Leukemia & Lymphoma Society Scholar Award.

Citation

Xu, Y et al, 鈥淎 TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia.鈥� Published online in Cancer Cell January 8, 2017.