Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study finds enzyme activity promotes rare form of leukemia, offers potential target for new drugs

22.04.2005


Scientists at the University of North Carolina at Chapel Hill have identified an enzyme that helps trigger the development of leukemia, a cancer of blood cells.



The enzyme hDOT1L activates a set of genes that plays a key role in the rare and largely incurable acute myeloid leukemia (AML). This disease affects less than 2 percent of the estimated 16,000 individuals diagnosed with acute leukemia nationwide each year. The discovery, based on research using bone marrow cells from mice, offers a potential target for new drugs against this form of leukemia, the researchers said.

The new findings appear in today’s (April 21) issue of the journal Cell. The report demonstrates that hDOT1L helps transform, or immortalize, bone marrow cells, causing their unrestrained growth, a hallmark of leukemia, the researchers said.


Dr. Yi Zhang, associate professor of biochemistry and biophysics at UNC’s School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center, led the study. Zhang is the university’s first Howard Hughes Medical Institute investigator, one of the most prestigious appointments among biomedical researchers.

"We demonstrate that not only is hDOT1L required for transformation of bone marrow cells, but, more importantly, that its enzymatic activity is required to maintain the transformed status," said Zhang. "That means if we have a way to prevent the activity of hDOT1L, then the affected cells of particular leukemia patients can be killed."

Zhang investigates a group of enzymes that modifies five core histone proteins forming the molecular scaffold that helps organize DNA within the nucleus of every cell. Histone modifications affect gene activity and include methylation, in which a methyl component is attached to the histone protein.

"The prevailing model is that methylation on histones serves as a docking site," Zhang said. "It will recruit proteins that ’read’ this histone modification, and it’s those proteins that directly have an impact on gene expression - either activating or silencing a gene."

As an enzyme that adds a methyl component to histone H3, hDOT1L activates the gene associated with that histone. Zhang and fellow researchers now provide evidence that in some leukemias, hDOT1L activates so-called Hox genes, whose increased activity is closely tied to AML.

Leukemia most often arises from a chromosomal translocation, a breaking and joining of two distinct chromosomes, that creates a hybrid gene. The product of the hybrid gene is called a "fusion protein," meaning that the newly formed gene encodes a protein made of fragments from each of the two genes that were fused together by the rearrangement.

Some leukemia patients carry rearrangements of a gene on chromosome 11 called the mixed lineage leukemia gene, or MLL. Translocations involving MLL are most often found in childhood leukemias and as a secondary cancer in adults who have undergone chemotherapy to treat a previous leukemia.

Individuals with MLL translocations have an especially poor prognosis, with less than a 50 percent survival rate.

"There are more than 40 proteins that have been found fused to MLL in leukemia patients, and different ones can cause leukemia by different mechanisms," Zhang said.

When MLL functions as it should, without a fusion partner, it binds to and controls the expression of Hox genes, which in turn control cell growth and maturation. Until now, the role of the MLL-AF10 fusion protein in causing leukemia was unknown.

"We show how at least one MLL fusion can lead to the over-expression of Hox genes in bone marrow cells. MLL-AF10 directs hDOT1L to the Hox genes, where it normally shouldn’t be, causing a different pattern of histone methylation and, therefore, extraordinarily high activity of the Hox genes," Zhang said.

Treatments used for AML patients have been largely ineffective against cells harboring the MLL-AF10 fusion protein, drawing attention to the need for a new medication.

Zhang’s study reveals that leukemia cells containing MLL-AF10 require hDOT1L to survive. When the researchers introduced into leukemia cells a defective form of hDOT1L, one that cannot methylate histone proteins, the cells were no longer able to grow. "This study highlights the potential of hDOT1L as a possible drug target," Zhang added.

L. H. Lang | EurekAlert!
Further information:
http://www.med.unc.edu

More articles from Life Sciences:

nachricht First line of defence against influenza further decoded
21.02.2018 | Helmholtz-Zentrum für Infektionsforschung

nachricht Helping in spite of risk: Ants perform risk-averse sanitary care of infectious nest mates
21.02.2018 | Institute of Science and Technology Austria

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

MEMS chips get metatlenses

21.02.2018 | Physics and Astronomy

International team publishes roadmap to enhance radioresistance for space colonization

21.02.2018 | Physics and Astronomy

World's first solar fuels reactor for night passes test

21.02.2018 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>