Featured Research

from universities, journals, and other organizations

Epigenetic pathway and new drug show promise in reversing a hard-to-treat childhood cancer

Date:
July 11, 2011
Source:
Children's Hospital Boston
Summary:
A difficult-to-treat form of childhood leukemia relies on changes in the structure of DNA -- so-called epigenetic changes -- to wreak genomic havoc within white blood cells, according to one of two new studies. Researchers also showed that a new drug that blocks these changes could deactivate cancer-promoting genes and halt the growth of this cancer.

A difficult-to-treat form of childhood leukemia relies on changes in the structure of DNA -- so-called epigenetic changes -- to wreak genomic havoc within white blood cells, according to one of two studies conducted by a research team at Children's Hospital Boston and Dana-Farber Cancer Institute. Together with collaborators from a biotechnology company, the same team also showed that a new drug that blocks these changes could deactivate cancer-promoting genes and halt the growth of this cancer.

These studies, reported in a pair of papers in the July 11, 2011 issue of Cancer Cell, are the first to therapeutically target a core epigenetic vulnerability in the subgroup of leukemias caused by a "reshuffling" or rearrangement of the mixed lineage leukemia (MLL) gene.

"We have known for a while that MLL leukemias arise from widespread alterations not in the genetic code itself, but in the structure of the DNA and the proteins associated with it," according to Scott Armstrong, MD, PhD, a pediatric oncologist at Children's and Dana-Farber. "We now show that these epigenetic changes indeed turn on cancer-promoting genes within white blood cells, and ultimately cause the leukemia.

"Even more importantly," he continued, "we show that we can reverse the process."

While childhood leukemia is one of the great success stories in cancer therapy, those caused by MLL gene rearrangements stand out as devastating exceptions. In these cancers, a portion of chromosome 11 (where the MLL gene resides) breaks off and fuses with parts of other chromosomes to create new fusion proteins. The fusion proteins subvert the normal function of the MLL gene and activate a set of leukemia-causing genes.

MLL gene rearrangements account for approximately 10 percent of children and adults diagnosed with acute lymphoblastic or acute myeloid leukemias; most of these patients do not respond well to standard leukemia treatments.

"The success rates for treating other childhood leukemias has reached 80 or 90 percent," Armstrong said. "However, we still only achieve about 50 percent success in treating MLL-rearranged leukemias. We need to find better ways of caring for these patients, and these results give us confidence that we are heading in the right direction."

Armstrong had previously shown that MLL-rearranged leukemia cells have a unique pattern of histone methylation, a specific kind of epigenetic modification, caused by an enzyme called Dot1l. This enzyme, which is recruited to cancer-promoting genes by the MLL-fusion protein, attaches a methyl group to a particular amino acid on a histone (a scaffolding protein that helps manage gene activation) called histone H3.

In the first of the two Cancer Cell papers, Armstrong, along with Kathrin Bernt, MD, and Andrew Kung, MD, PhD, of Children's and Dana-Farber, confirms that genes targeted by a MLL fusion protein called MLL-AF9 are associated with inappropriately methylated histone H3 proteins. By genetically inactivating Dot1l, the team could eliminate the MLL-specific histone methylation and gene expression patterns in cells from a mouse model of the disease. In addition, they found that mice injected with leukemia cells lacking Dot1l did not develop leukemia, in contrast to those injected with leukemia cells possessing active Dot1l.

"Our previous work suggested that Dot1l was the culprit behind the abnormal methylation patterns in MLL-rearranged cells," Armstrong noted. "We now know that these leukemias fully rely on this enzyme and the methylation pattern it generates in order to persist and grow.

"While methylation tags on histones are very difficult to manipulate directly," he added, "Dot1l is much easier to target therapeutically."

The second Cancer Cell paper, co-authored by Armstrong, Bernt, Kung and collaborators at the biotechnology company Epizyme, takes the Dot1l findings a step further by showing that a small molecule called EPZ004777, which inhibits the enzyme, does indeed eliminate the abnormal methylation pattern in MLL cells. In cell-based laboratory models, the effects of treatment with EPZ004777 mirrored those obtained by inactivating Dot1l in genetically engineered "knockout" mice, while selectively causing MLL-rearranged leukemia cells to die off in about two weeks' time. Moreover, mice with MLL-rearranged leukemia showed increased survival when treated with EPZ004777.

"The oncology field is very excited about epigenetic inhibition right now," Armstrong said. "Enzymes like Dot1l that influence epigenetics are overactive in many cancers. What we've done is show that we can block one of these enzymes and get very specific anti-tumor activity in a previously very hard-to-treat disease."

The two studies were supported by grants from the National Cancer Society, the Leukemia and Lymphoma Society, Gabrielle's Angel Foundation, the National Cancer Institute, the National Heart Lung and Blood Institute, and the William Lawrence and Blanche Hughes Foundation.


Story Source:

The above story is based on materials provided by Children's Hospital Boston. Note: Materials may be edited for content and length.


Journal References:

  1. Scott R. Daigle, Edward J. Olhava, Carly A. Therkelsen, Christina R. Majer, Christopher J. Sneeringer, Jeffrey Song, L. Danielle Johnston, Margaret Porter Scott, Jesse J. Smith, Yonghong Xiao et al. Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor. Cancer Cell, Volume 20, Issue 1, 53-65, 12 July 2011 DOI: 10.1016/j.ccr.2011.06.009
  2. Kathrin M. Bernt, Nan Zhu, Amit U. Sinha, Sridhar Vempati, Joerg Faber, Andrei V. Krivtsov, Zhaohui Feng, Natalie Punt, Amanda Daigle, Lars Bullinger et al. MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L. Cancer Cell, 20(1) pp. 66 - 78; 12 July 2011 DOI: 10.1016/j.ccr.2011.06.010

Cite This Page:

Children's Hospital Boston. "Epigenetic pathway and new drug show promise in reversing a hard-to-treat childhood cancer." ScienceDaily. ScienceDaily, 11 July 2011. <www.sciencedaily.com/releases/2011/07/110711131326.htm>.
Children's Hospital Boston. (2011, July 11). Epigenetic pathway and new drug show promise in reversing a hard-to-treat childhood cancer. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2011/07/110711131326.htm
Children's Hospital Boston. "Epigenetic pathway and new drug show promise in reversing a hard-to-treat childhood cancer." ScienceDaily. www.sciencedaily.com/releases/2011/07/110711131326.htm (accessed October 20, 2014).

Share This



More Health & Medicine News

Monday, October 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

How Nigeria Beat Its Ebola Outbreak

How Nigeria Beat Its Ebola Outbreak

Newsy (Oct. 20, 2014) The World Health Organization has declared Nigeria free of Ebola. Health experts credit a bit of luck and the government's initial response. Video provided by Newsy
Powered by NewsLook.com
Another Study Suggests Viagra Is Good For The Heart

Another Study Suggests Viagra Is Good For The Heart

Newsy (Oct. 20, 2014) An ingredient in erectile-dysfunction medications such as Viagra could improve heart function. Perhaps not surprising, given Viagra's history. Video provided by Newsy
Powered by NewsLook.com
Ebola Worries End for Dozens on U.S. Watch Lists

Ebola Worries End for Dozens on U.S. Watch Lists

Reuters - US Online Video (Oct. 20, 2014) Forty-three people who had contact with Thomas Eric Duncan, the first person diagnosed with Ebola in the U.S., were cleared overnight of twice-daily monitoring after 21 days of showing no symptoms. Rough Cut (no reporter narration). Video provided by Reuters
Powered by NewsLook.com
Fauci: Ebola Protocols to Focus on Training

Fauci: Ebola Protocols to Focus on Training

AP (Oct. 20, 2014) Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, says he expects revised CDC protocols on Ebola to focus on training, observation and ensuring health care workers are more protected. (Oct. 20) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins