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:5/27/2016)... ... 27, 2016 , ... Aimed at nurses and employees in ... courtesy of leaders in the nursing and health care industry. It also provides ... and associations—namely Jones & Bartlett Learning. , Jones & Bartlett Learning is adding ...
(Date:5/26/2016)... ... 2016 , ... Despite last week’s media reports hinting at a June rate ... until March 2017 for an interest rate increase, according to Rajeev Dhawan of the ... “The Federal Open Market Committee (FOMC) dot charts are of interest to the press ...
(Date:5/26/2016)... St. Louis, Missouri (PRWEB) , ... May 26, ... ... optimal cost, quality and clinical outcomes, hosted members and suppliers for its inaugural ... with a focus on their mission of elevating the operational health of America’s ...
(Date:5/26/2016)... ... May 26, 2016 , ... The Woodlands at ... offering a new model of care for living and healing, celebrated its grand opening, ... Life in a Real Home provided by Empowered Staff. , “This is an incredibly ...
(Date:5/26/2016)... ... May 26, 2016 , ... ... solutions for drugs, biologics, consumer health and global clinical supply services, today announced ... to support the company’s continued investment and strategic growth plans in the Asia ...
Breaking Medicine News(10 mins):
(Date:5/26/2016)... NASHVILLE, Tenn. , May 26, 2016 ... provider of software and analytics, network solutions ... healthcare, today announced it entered into a ... leading provider of outpatient software solutions and ... surgery centers, specialty hospitals and rehabilitation clinics ...
(Date:5/25/2016)... Germany and GERMANTOWN, Maryland ... (NASDAQ: QGEN ; Frankfurt Prime Standard: QIA) today ... co-development agreement with Therawis Diagnostics GmbH to develop and commercialize ... develop and market PITX2 as a marker to predict effectiveness ... cancer patients. "We are pleased to partner with ...
(Date:5/25/2016)... Va. , May 25, 2016  Granger Diagnostics ... sequencing test for wounds and infections. This test ... parasites, and select viruses. The test requires only ... David G. Bostwick , ... testing to facilitate wound healing: "We are excited ...
Breaking Medicine Technology: