Navigation Links
Tackling a hard-to-treat childhood cancer by targeting epigenetic changes
Date:11/3/2008

A very difficult-to-treat child leukemia may benefit from the discovery of a small but potent epigenetic change that launches the cancer but could potentially be reversed relatively easily, preventing cancer-promoting genes from being turned on. The study, led by researchers at Children's Hospital Boston and the Dana-Farber Cancer Institute, is the cover article in the November 4 issue of Cancer Cell.

While cure rates for the major types of childhood leukemia are now about 80 percent, they are much lower for patients with a subtype of acute lymphoblastic leukemia (ALL) known as MLL-AF4, which accounts for 5 percent of all ALLs but 70 percent of ALLs striking infants. Children with this form of leukemia suffer rapid relapses and have a cure rate of just under 50 percent with chemotherapy.

"MLL-AF4 leukemias are very difficult to treat and in desperate need of new therapeutic approaches," says senior investigator Scott Armstrong, MD, PhD, of Children's and Dana-Farber. Like other other leukemias, the disease leads to abnormally high numbers of immature, dysfunctional white blood cells that crowd out the bone marrow, interfering with its ability to produce healthy blood cells.

The researchers, led by Armstrong, Andrei Krivtsov, PhD and Zhaohui Feng, also of Children's and Dana-Farber, first developed a mouse model of MLL-AF4, which had eluded scientists in the past. They then showed that the abnormal "fusion" protein that characterizes the disease, also known as MLL-AF4, goes to the cell's DNA and causes abnormal modification of one of the histones, "scaffolding" proteins that give chromosomes their shape and help control gene activation. As a result of this epigenetic change, chromosome structure is altered. This jump-starts activity of a diverse group of genes, including some known to be critical in initiating leukemia.

Studying samples from children with MLL-AF4 leukemias, the team made the same observations. "The fusion protein modifies histones and turns on genes that are not supposed to be turned on, and that initiate the development of the cancer," says Armstrong. "If you could inhibit that abnormal histone modification, you might be able to reverse the tumorigenic properties of the fusion protein."

It appears this inhibition may be relatively simply to accomplish. The researchers went on to demonstrate that MLL-AF4 does its evil work by recruiting an enzyme called DOT1L, which modifies the histone H3 by attaching a methyl group to a particular amino acid. While MLL-AF4 itself would be difficult to target chemically, enzymes are generally fairly easy to target with small-molecule drugs. Simply by inhibiting DOT1L, a variety of critical genes that contribute to the malignancy could potentially be inhibited.

A pharmaceutical DOT1L inhibitor hasn't yet been found, but when the researchers suppressed DOT1L indirectly through RNA interference techniques, the abnormally activated genes were turned off.

"Based on these data, we are searching for small molecules or drugs that inhibit DOT1L," says Armstrong. "Reversal of histone modifications could be an important therapeutic approach for this and potentially other cancers."

Armstrong notes that there are already drugs in clinic that target enzymes that modify histones, namely histone deacetylase (HDAC) inhibitors, which are used to treat a kind of lymphoma and are being tested in other cancers.


'/>"/>

Contact: Rob Graham
rob.graham@childrens.harvard.edu
617-919-3110
Children's Hospital Boston
Source:Eurekalert  

Related medicine news :

1. Tackling Triglycerides: 8 Ways to Solve a Big Fat Problem, From the Harvard Heart Letter
2. Lack of political will and the subordination of women are major barriers to tackling AIDS
3. Southern California Parents and Kids Take Healthy Steps in Tackling Childhood Obesity
4. Public Health Leaders Unveil Blueprint for Tackling Climate Change
5. Tackling depression in cancer patients can extend life
6. Experts to share how research is tackling cancer
7. Tackling Obesity Through Education and FUNdraising
8. Tackling Hard-to-treat Childhood Cancer by Targeting Epigenetic Changes
9. Revolutionary New Technique Uses Onyx to Fill Hard-To-Treat Aneurysms
10. Relaxation training may improve control of hard-to-treat systolic hypertension
11. Blood-clotting protein modified for people with hard-to-treat hemophilia
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Tackling a hard-to-treat childhood cancer by targeting epigenetic changes
(Date:4/29/2016)... ... 29, 2016 , ... Our bodies are bombarded daily by environmental and lifestyle ... these stressors is to adopt a more healthful diet, but too many people think ... certified Holistic Nutritionist and the creator of the Newport Beach Cleanse and 14-Day Eating ...
(Date:4/29/2016)... (PRWEB) , ... April 29, 2016 , ... ... optimistic healthcare awareness and author of best seller "LOVE, MEDICINE and MIRACLES") addresses ... Monday, May 2, 2016 and podcasted thereafter . Dr. Bernie Siegel, author ...
(Date:4/29/2016)... ... April 29, 2016 , ... Coast Dental Fort Stewart ... at its new location in the Exchange Furniture Mall at 112 Vilseck Road in ... 50-inch Samsung Smart TV. Plus attendees will have the opportunity to meet general dentists ...
(Date:4/29/2016)... ... 2016 , ... The Wharton School of the University ... of the 2016 Wharton Business Plan Competition —as well as the Wharton ... the Committee Award for Most ‘Wow Factor,’ making them the first team in ...
(Date:4/29/2016)... Toronto, ON (PRWEB) , ... April 29, 2016 ... ... GlutenFreeCoupons.ca and the Canadian Celiac Association (CCA), is pleased to announce the launch ... about gluten-free products, nutritional articles, recipes, and more. The purpose of the ...
Breaking Medicine News(10 mins):
(Date:4/29/2016)... 2016 Automation is one of ... to the growing demands for productivity in speed, accuracy, ... systems are already adept of a wide range of ... manual labor. Instrumentation continues to evolve, and is poised ... a few years ago. Originally used mostly by the ...
(Date:4/28/2016)... , April 28, 2016 ... "Global Plastic Surgery Products Market 2016-2020" report ... ) , The global plastic surgery ... of 9.47% during the period 2016-2020. , ,The growing ... leading to the growth of the market. Lasers are ...
(Date:4/28/2016)... NEW YORK , April 28, 2016  The ... reached 275 million dollars, according to Kalorama Information and ... includes typing, immunoassays and nucleic acid testing.  The healthcare ... had made progress in developing blood collection stations and ... was made in Kalorama Information,s report, Blood ...
Breaking Medicine Technology: