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University of Cincinnati
Preclinical research indicates that a protein associated with obesity is also involved in the development of acute myeloid leukemia (AML) and may affect AML patients’ response to treatment.
Researchers found evidence to suggest that the fat mass- and obesity-associated protein (FTO) regulates the expression of a set of genes through a mechanism involving RNA modification, thereby increasing the reproduction of leukemia cells and prohibiting drug response.
Jianjun Chen, PhD, of the University of Cincinnati in Ohio, and his colleagues conducted this research and reported the findings in Cancer Cell.
The team noted that N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in messenger RNAs (mRNAs) in genes. And they found that FTO, an m6A demethylase, plays a critical oncogenic role in AML.
The researchers made this discovery by analyzing 2 microarray datasets of samples from AML as well as samples from control subjects.
The team found that FTO was highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.
The high level of FTO expression contributed to leukemia cells multiplying and surviving and also promoted the development of AML in animal models and the non-response of AML cells to therapeutic agents.
Additionally, the researchers found that genes like ASB2 and RARA, which were reported to inhibit leukemia cell growth and/or mediate the response of leukemia cells to therapeutic agents, were suppressed in the AML samples with higher FTO expression.
The suppression of these genes was attributed to FTO-controlled decreased stability of their mRNA and was connected to FTO’s m6A demethylase activity.
“Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia,” Dr Chen said. “In addition, given the functional importance of FTO in the formation of leukemia and drug response, targeting FTO signaling may present a new therapeutic strategy to treat leukemia.”
“As FTO may also play a cancer-promoting role in various types of solid tumors, besides leukemia, our discoveries may have a broad impact in cancer biology and cancer therapy. Further studies are needed to advance our understanding of the critical role of FTO in various types of cancers and to develop more effective novel therapeutic strategies based on such understanding to treat cancers.”
