A study of gene expression in leukemia cells has actually identified an RNA binding healthy protein that plays an crucial role in driving the improvement of cancer. The healthy protein is normally energetic in fetal tissue and switched off in adults, yet it is reactivated in some cancer cells. This expression pattern makes it an attractive target for cancer-fighting drugs, since blocking its activity is unlikely to induce significant edge effects.
The brand-new study, published March 14 in the Journal of Clinical Investigation, focused on a particularly aggressive form of B-cell acute lymphoblastic leukemia (B-ALL), the a lot of prevalent kind of leukemia in kids and young adults. A group led by scientists at UC Santa Cruz and UCLA located an overabundance of the RNA binding healthy protein known as IGF2BP3 in the cancer cells of this subset of B-all of patients.
“This protein, IFG2BP3, has actually been correlated along with several types of malignancies and along with the worst prognoses,” said coauthor Jeremy Sanford, associate professor of molecular, cell, and developmental biology at UC Santa Cruz. “Exactly what is exciting concerning this study is that it goes beyond correlation and shows causation, since we demonstrated for the very first time that aberrant expression of this healthy protein is sufficient to induce pathology.”
Oncogenes
The researchers identified genes that are straight regulated by this RNA binding protein, and several of them transform out to be oncogenes that have actually currently been implicated in cancer. In particular, the healthy protein increases the expression of a well-characterized oncogene called MYC, which in transform regulates a large lot of genes involved in cell proliferation.
Compared to others proteins involved in regulating gene activity, RNA binding proteins have actually not been well studied. As quickly as a gene is turned on or “expressed,” an RNA copy is earned of the gene’s DNA sequence, and the genetic code carried by this “messenger RNA” is after that translated in to a healthy protein that carries out some cellular function. several factors are involved in controlling which genes get hold of transcribed in to messenger RNA and when, yet RNA binding proteins interact along with the messenger RNA itself to regulate gene expression after transcription has actually occurred. Scientists are just start to unravel the complexity of this post-transcriptional regulation of gene expression.
In the case of IGF2BP3 and B-cell leukemia, the overall effect of the RNA binding healthy protein is to promote the proliferation of B cells by shifting the expression of a large lot of genes, Sanford said.
Stem cells
Leukemia begins in the “hematopoietic” stem cells in the bone marrow that offer rise to all of the various kinds of mature blood cells. A lot of genetic alterations can easily induce abnormal white blood cells to proliferate and crowd out the regular blood cells. Sanford’s collaborator at UCLA, Dinesh Rao, was studying B-all of cases involving chromosomal rearrangements of the mixed lineage leukemia (MLL) gene, which accounts for concerning 5 percent of B-all of cases and is associated along with inadequate prognosis and increased risk of early relapse after treatment.
After Rao’s lab identified IGF2BP3 as among the top dysregulated genes in these cases, they began functioning along with Sanford’s lab to determine which genes were being straight regulated by IGF2BP3. Sanford and Rao have actually been friends because they were undergraduates, and Rao knew that Sanford’s lab was among the couple of making use of a technique that can easily capture RNA molecules bound to a certain protein. Called personal nucleotide resolution crosslinking immunoprecipitation (iCLIP), the technique enabled Sanford’s lab to identify IGF2BP3 binding sites in several hundred RNA transcripts in two B-all of cell lines. They additionally showed that IGF2BP3 enhanced the expression of MYC and others oncogenes in hematopoietic stem cells.
Studying its effects in mice, the researchers located 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.
“Knowing its mechanism of action is crucial for thinking concerning therapeutics that may interfere along with the action of this healthy protein in disease,” Sanford said. “One opportunity is an RNA-based therapeutic that could sequester the healthy protein and maintain it from binding to RNA transcripts. That would certainly be a method to motivate the expression of several genes involved in the proliferation of cancer cells.”
The lead authors of the study are Jayanth Palanichamy and Tiffany Tran at UCLA and Jonathan Howard at UC Santa Cruz. others coauthors, along with Sanford and Rao, consist of Jorge Contreras, Thilini Fernando, and Weihong Yan at UCLA; Timothy Sterne-Weiler and Sol Katzman at UC Santa Cruz; Masoud Toloue at Bioo Scientific Corporation; and Giuseppe Basso and Martina Pigazzi at the University of Padova, Italy. This research was supported by grants from the National Institutes of Healthiness and the Santa Cruz Cancer Incentive Group.
