Science News
from research organizations

Locking up an oncogenic transcription

Date:
April 1, 2015
Source:
University of Massachusetts Medical School
Summary:
A novel molecule designed by scientists inhibits progression of a hard-to-treat form of recurring acute myeloid leukemia in patient tissue. The small molecule is one of the first designed to specifically target a cancer-causing transcription factor.
Share:
FULL STORY

A novel molecule designed by scientists at the University of Massachusetts Medical School and the University of Virginia inhibits progression of a hard-to-treat form of recurring acute myeloid leukemia (AML) in patient tissue. The small molecule is one of the first designed to specifically target a cancer-causing transcription factor. Previously thought to be an undruggable target, this strategy may be used to design other novel molecules that can specifically inhibit cancer-causing transcription factors. Details of the work were published in Science.

Transcription factors are single- or multi-protein complexes that regulate transcription of DNA into messenger RNA and gene expression by binding to regions on the genome next to a gene. Mutations in transcription factors can result in altered gene expression programs that give way to new, cancer-causing functions. Although these aberrant transcription factors are promising targets for new therapeutics, the complexity of interrupting very specific protein-to-protein interactions has made it difficult to find small molecules or design drugs that treat these cancers.

"When we look at inhibitors, they usually target an enzyme or receptor. There aren't a lot of good examples of transcription factor inhibitors in clinical trials," said Lucio H. Castilla, PhD, associate professor of molecular, cell and cancer biology and co-leader of the study. "Here, we've used our extensive knowledge of a mutant transcription factor found in a subset for acute myeloid leukemia patients to design a molecule that can specifically sequester only the oncogenic mutant. This leaves the normal transcription factor to bind to the DNA and restore gene expression."

Acute myeloid leukemia causes a rapid growth in abnormal white blood cells that accumulate in the bone borrow and interfere with the production of red blood cells. It is the most common form of adult leukemia and survival rates vary depending on specific genetic subsets. Typical treatment involves nonselective chemotherapy, but that can be taxing on some populations, especially the elderly. Therapeutic approaches that target specific genetic anomalies have the potential to be less toxic and yield better results.

AML patients with an inversion on chromosome 16 (known as inv(16) AML) typically respond to initial chemotherapy treatment, but recurrences are likely in a fraction of cases. Leukemia in these patients is caused by a small reversal of the DNA sequence on chromosome 16 that combines a gene which controls production of blood cells and one involved in muscle physiology. When healthy, the core-binding factor-beta (CBFB) protein typically binds with the RUNX protein to form a transcription factor that regulates a number of genes that control production of red and white blood cells. In AML cells with inv(16), the CBFB gene is fused with the smooth muscle myosin heavy chain (SMMHC) gene, and the activity of the CBFB-SMMHC fusion protein causes leukemia.

John H. Bushweller, PhD, a professor of biochemistry at the University of Virginia, screened a library of small molecules and found that the molecule AI-4-57 inhibited the binding of RUNX and CBFB-SMMHC. However, the activity of this molecule was not enough to have a therapeutic effect; by only treating a portion of the AML cells, enough would be left behind for the cancer to return and be resistant to further chemotherapy.

To overcome this problem, Castilla and Bushweller established a collaboration to modify the initial compound to specifically target only the mutant transcription factor (CBFB-SMMHC ) while leaving the normal one (CBFB) being produced by the other copy of chromosome 16 free to do its job of regulating blood cell production.

Taking advantage of the structural differences between the mutant and normal protein, the researchers were able to devise a new compound having the effect they sought. Because normal CBFB is monomeric and CBFB-SMMHC is oligomeric, they developed a bivalent version of the initially screened compound -- AI-4-57. After further refinement, the new drug AI-10-49 prolonged the survival rate of mice with inv(16) AML and was successful in treating in vitro leukemia lines taken from patients.

The polyvalent strategy may serve as a template for new drug discovery efforts focused on selective modulation of aberrant fusion proteins arriving from chromosomal translocation events, wrote Angela N. Koehler, PhD, assistant professor of biological engineering at the Massachusetts Institute of Technology, in a review accompanying the study. This study also serves as a "proof of concept for targeted therapies aimed at dysregulated transcription and should inspire the development of additional directed approaches to control aberrant transcription factor function in cancer and other diseases."

The next step for Castilla's team is to better understand how the newly designed molecule directs the cells expressing CBFB-SMMHC to die while spearing the normal cells of the patient.


Story Source:

Materials provided by University of Massachusetts Medical School. Note: Content may be edited for style and length.


Journal Reference:

  1. A. Illendula, J. A. Pulikkan, H. Zong, J. Grembecka, L. Xue, S. Sen, Y. Zhou, A. Boulton, A. Kuntimaddi, Y. Gao, R. A. Rajewski, M. L. Guzman, L. H. Castilla, J. H. Bushweller. A small-molecule inhibitor of the aberrant transcription factor CBF -SMMHC delays leukemia in mice. Science, 2015; 347 (6223): 779 DOI: 10.1126/science.aaa0314

Cite This Page:

University of Massachusetts Medical School. "Locking up an oncogenic transcription." ScienceDaily. ScienceDaily, 1 April 2015. <www.sciencedaily.com/releases/2015/04/150401215810.htm>.
University of Massachusetts Medical School. (2015, April 1). Locking up an oncogenic transcription. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2015/04/150401215810.htm
University of Massachusetts Medical School. "Locking up an oncogenic transcription." ScienceDaily. www.sciencedaily.com/releases/2015/04/150401215810.htm (accessed May 23, 2017).

RELATED STORIES