New evidence from researchers at the University of Cincinnati (UC) College of Medicine has indicated that a protein called FTO, which has been associated with obesity, has a role in the development of leukemia, as well as how drugs respond to it. The work could aid in the development of more effective therapies for the disease. The study, led by Jianjun Chen, an Associate Professor in the Department of Cancer Biology at UIC, has been published in Cancer Cell.
In 2011, a co-senior author of this paper, Dr. Chuan He, demonstrated that FTO can remove a type of RNA modification, N6-methyladenosine or m6A RNA methylation. The m6A modification has been shown to be the most common type of alteration to messenger RNAs (mRNAs), which act as an intermediary between genes and the proteins they code for. Cells use RNA modifications to control gene expression. This work has shown that the m6A modification is reversible, and reinforced the likelihood that it has significant biological importance.
"Recent studies have shown that m6A modification in mRNAs or non-coding RNAs plays critical roles in virtually all major normal biological processes such as tissue development and stem cell self-renewal and differentiation,” said Chen. However, little is known about the biological importance of m6A modification in the regulation of cancer-causing genes and/or tumor-suppressing genes in the development of tumors."
In this report, the investigators utilized a microarray of acute myeloid leukemia (AML) and control samples. They discovered that FTO was expressed at high levels in subtypes of leukemias that carried mutations in certain genes as well as those that had genetic exchange between chromosomes – chromosome crossover. Increased expression of FTO contributed to the proliferation of cancer cells, supported the growth of leukemia in animal models, and was seen in cases that were not responsive to therapeutics.
The investigators also found that genes that have been reported to inhibit the growth of leukemia, ASB2 and RARA, are suppressed in the AML samples that had a high level of FTO expression. It is thought that the m6A demthylase action of FTO reduces the stability of the mRNAs of those genes.
"Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia," said Chen. "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."
If you would like to know more about the m6A modification and how it relates to diabetes and cancer, check out the following talk from Professor Tsvee Lapidot, Incumbent of the Edith Arnoff Stein Professorial Chair in Stem Cell Research in the Immunology Department of the Weizmann Institute of Science. Around the fifth minute the talk gets going, when RNA modifications are introduced, and around minute ten, FTO is mentioned and the relationship between the m6A modifications and disease is discussed later in the talk.