An RNA binding protein promotes the development of MLL-rearranged B-cell acute lymphoblastic leukemia (B-ALL), according to research published in The Journal of Clinical Investigation.
Researchers found an overabundance of the protein, IGF2BP3, in MLL-rearranged B-ALL.
They also identified genes that are directly regulated by IFG2BP3, and many of them turned out to be oncogenes that have already been implicated in cancers.
The overall effect of IFG2BP3 in MLL-rearranged B-ALL is to promote the proliferation of B cells by shifting the expression of a large number of genes, explained study author Jeremy Sanford, PhD, of the University of California Santa Cruz.
“This protein, IFG2BP3, has been correlated with many types of malignancies and with the worst prognoses,” he noted. “What is exciting about this study is that it goes beyond correlation and shows causation, because we demonstrated, for the first time, that aberrant expression of this protein is sufficient to induce pathology.”
This research began in the lab of Dinesh Rao, PhD, an assistant professor at the University of California Los Angeles who was studying MLL-rearranged B-ALL.
After researchers in Dr Rao’s lab identified IGF2BP3 as one of the top dysregulated genes in this malignancy, they began working with Dr Sanford’s lab to figure out which genes were being directly regulated by IGF2BP3.
Dr Sanford’s lab was among the few using individual nucleotide resolution crosslinking immunoprecipitation (iCLIP), a technique that can capture RNA molecules bound to a particular protein.
iCLIP enabled the researchers to identify IGF2BP3 binding sites in several hundred RNA transcripts in 2 B-ALL cell lines.
The work also revealed that IGF2BP3 enhanced the expression of MYC and other oncogenes in hematopoietic stem cells.
In experiments with mice, the researchers found that overexpression of IGF2BP3 in the bone marrow leads to proliferation of hematopoietic stem cells and B-cell progenitors, reproducing some features of MLL-rearranged B-ALL.
“Understanding its mechanism of action is important for thinking about therapeutics that might interfere with the action of this protein in disease,” Dr Sanford said.
“One possibility is an RNA-based therapeutic that could sequester the protein and keep it from binding to RNA transcripts. That would be a way to influence the expression of many genes involved in the proliferation of cancer cells.”
