Apr 21 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.