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OSU Study Links Two microRNAs With the Oncogene Responsible for B-Cell Leukemia

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Researchers from Ohio State University last week published data linking two microRNAs to the regulation of Tcl1, an oncogene associated with the aggressive form of B-cell chronic lymphocytic leukemia.
The findings, which were published in the Dec. 15 issue of Cancer Research, mark the latest addition to a growing body of evidence linking miRNAs, in this case miR-29 and miR-181, to various diseases.
 
According to Yuri Pekarsky, assistant professor of human cancer genetics at OSU and lead author on the paper, B-CLL is the most common form of human leukemia and can be divided into three classes: indolent, aggressive, and aggressive with a deletion of chromosome 11q.
 
Previously, Carlo Croce, another OSU researcher and paper co-author, had shown that deletion of two miRNAs causes over-expression of the antiapoptotic B cell lymphoma 2 protein, which in turn leads to indolent B-CLL, Pekarsky told RNAi News this week.
 
Follow-on work by Croce in animal models of B-CLL indicated that Tcl1 over-expression is associated with aggressive B-CLL, he noted. “Because we already knew that miR-15 and miR-16 are important in indolent B-CLL, we thought that maybe in aggressive B-CLL miRNAs are also important [and] we decided to find out if the expression of Tcl1 is regulated by miRNAs.”
 
To do so, Pekarsky and his colleagues conducted miRNA profiling in samples of the three types of B-CLL.
 
“MicroRNA microchip experiments revealed that [the] three groups of B-CLL show significant characteristic differences in microRNA expression pattern,” the researchers wrote in the Cancer Research paper, adding that the results of further experimentation indicated that “Tcl1 over-expression correlates with aggressive B-CLL phenotype and 11q deletions.”
 
The researchers then compiled a list of miRNA signatures corresponding to each type of B-CLL and compared it with a list of Tcl1-targeting miRNA candidates obtained using the Bielefeld University Bioinformatics Server RNAhybrid software and the Wellcome Trust Sanger Institute’s miRBase database.
”Then we checked one list against the other list and found that several microRNAs were on both of them,” including miR-29 and miR-181, Pekarsky said.
 
These two miRNAs were found to be down-regulated in aggressive B-CLLs with 11q deletions, and it has previously been shown that expression of miR-29 family members could discriminate between CLL samples with good and bad prognosis, the researchers wrote.
 
Additional work revealed that miR-29 and miR-181 “target Tcl1 expression at mRNA and protein levels,” they noted, adding that “expression levels of miR-29 and miR-181 generally inversely correlated with Tcl1 expression in the … samples.”
 

“MicroRNA microchip experiments revealed that [the] three groups of B-CLL show significant characteristic differences in microRNA expression pattern.”

The researchers note in their Cancer Research paper that “the fact that neither miR-29 nor miR-181 is located at 11q suggests that the region may contain an important regulator of the expression of these two [miRNAs].”
They also pointed out that “of the four down-regulated microRNAs in aggressive B-CLL, three are different isoforms of miR-29 … strongly suggesting that miR-29 and TCL1 interactions play an important role in the pathogenesis of aggressive B-CLL. Interestingly, miR-181 is differentially expressed in B cells and TCL1 is mostly a B-cell-specific gene,” they added. “This suggests that Tcl1 might be a target of miR-181 not only in B-CLL cells but also in normal B-lymphocytes.”
 
“Additional studies are necessary to determine whether there is an inverse correlation between TCL1 and miR-181 expression at different stages of B-cell maturation,” the research team wrote. “Because miR-29 and miR-181 are natural Tcl1 inhibitors, these miRs may be candidates for therapeutic agents in B-CLL-overexpressing Tcl1.”
 
Pekarsky said that his next step is to “see if we can treat B-CLL in mice using these microRNAs.”
 
“There are several published methods of doing this,” including injecting the animals with either modified double-stranded RNA or microRNA precursors, he said, noting that “I would expect in one year we will start testing this.”