Researchers at the University of California - Santa Barbara (UCSB) have discovered a molecular pathway that may explain how an acute myeloid leukemia (AML) develops.
The research team described how a certain mutation in DNA disrupts cellular function in patients with AML.
The enzyme is a protein called DNMT3A, which leads to changes in how the DNA of AML patients is methylated, or tagged.
Norbert Reich, professor in the Department of Chemistry and Biochemistry at UCSB, was already studying that particular enzyme with his research group, so they began to study the disease process of AML at the cellular level.
Mr Reich explained that tagging is a way of reading DNA at the cellular level. This falls within an area of study called epigenetics, a process that occurs on top of genetics.
Mr Reich explained that with epigenetics, instead of only having DNA sequence coding for certain genes, there is an epigenetic process, with another layer of information on top of the genetic process. In this case, that information is the tagging by the methyl groups.
“If you really think about it, this is part of the answer as to how your cells can be so different and yet they all have the same DNA,” said Reich.
“You have the same genome in every one of your cells, but you do not have the same epigenome, which is basically the methylation pattern, the tagging pattern. That is different in every type of your cells. And the way this relates back to cancer, with leukemia, in those patients, the tagging is messed up. The patterns are not correct. Our big contribution to that is we’ve explained how the mutations in the enzyme could lead to that disruption of the tagging pattern.”
The research team developed a test to demonstrate that the mutant enzymes in AML can only work on DNA for short distances. As a result, the precise methylation patterns of a healthy cell are disturbed, resulting in genes being turned on at the wrong place and time, which in turn can initiate the growth of cancerous cells.
The team found that the mutation AML patients have causes a certain complex of four proteins to be disrupted. “The surprise was that the disruption doesn’t stop the enzyme from being active; it doesn't stop the enzyme from tagging the DNA,” said Reich.
“Instead, it stops the way it can do it. Instead of going to your DNA and tagging an entire region of chromosome, it goes there, does one thing, and leaves. That process, that change, is what we see in the AML patients. So we think we have a molecular explanation for this disease.”
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