Gene within gene drives acute myeloid leukemia, says new study
New research suggests that it is a smaller gene embedded inside a larger gene already linked to poor survival of patients with acute myeloid leukemia that truly drives progression of the disease.
Researchers from the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) report their findings in the journal Science Signaling.
Acute myeloid leukemia (AML) is a cancer that starts in cells that would normally develop into various blood cells. It is generally a disease of older people - the average age of a patient with AML is about 66 years.
The American Cancer Society estimates that in 2014, about 18,860 new cases of AML will be diagnosed in the US and there will be about 10,460 deaths from the disease.
High expression of a gene called BAALC (short for brain and acute leukemia, cytoplasmic and pronounced "ball C") is known to be linked with poor survival of people with AML.
BAALC has a smaller gene - called microRNA-3151 - embedded inside it that is also known to be active in AML.
The new study shows that of the two, the smaller gene is the major driver of AML, and it also suggests a drug that blocks it.
While both genes play a role, it is miR-3151 that really drives AML
Principal investigator and co-senior author Albert de la Chapelle, professor of Medicine and the Leonard J. Immke Jr. and Charlotte L. Immke Chair in Cancer Research at OSUCCC - James, says:
"When both genes are highly expressed, it means a bad prognosis for patients, but our experiments indicate that it is high expression of miR-3151 that really matters. Overexpression of BAALC alone had only limited cancer-causing activity."
Using human cell cultures and mice, he and his colleagues investigated the extent to which overexpression of miR-3151 and BAALC contribute to disease progression in older patients with cytogenetically normal AML.
They found the smaller gene spurs the development of AML by blocking a tumor suppressor gene called TP53 that normally causes suspect cells with serious DNA damage to self-destruct.
Co-senior author Clara D. Bloomfield, Distinguished University Professor and Ohio State University Cancer Scholar, explains the effect the smaller gene has:
"When miR-3151 blocks TP53 in the tumor cells, it enables the cells to survive, divide and grow faster."
MiR-3151 may also be important factor in solid tumors
Prof. Bloomfield says they found miR-3151 also spurs growth in malignant melanoma cells in the same way, indicating it might be an important factor in the growth of solid tumors.
They also found that miR-3151 can be active on its own, independent of the host gene, and that it directly targets TP53 and seven other genes in the TP53 pathway.
In a final part of their study, the team showed that the proteasome inhibitor bortezomib reduced overexpression of miR-3151, pointing to it as a potential way to treat overexpression of the small gene.
MiR-3151 belongs to a class of regulatory molecules called microRNAs that help to control protein production. There are several hundred known human microRNAs of which around a third are embedded in host genes in short stretches of DNA called introns.
"We know very little about how microRNAs located within introns are regulated and how they interact with their host genes. These findings provide an important example of that interaction," says first author and postdoctoral researcher Dr. Ann-Kathrin Eisfeld.Funds from the NIH/National Cancer Institute, the Coleman Leukemia Research Foundation, and the Pelotonia Fellowship Program helped finance the study.
Medical News Today recently reported a study published in Nature that found a link between a leukemia gene and a new childhood growth disorder that the researchers named "DNMT3A overgrowth syndrome" after the gene. However, they say the mutations in DNMT3A that link to the growth disorder are not the same as those that link to leukemia, and having the disorder does not increase the risk of cancer.
Written by Catharine Paddock PhD
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