Jason Mendler, MD
How can something so small have such a profound biological effect? MicroRNAs (miRNAs) are small RNA molecules (average 22 nucleotides) that are post-transcriptional regulators that bind to complementary sequences in the three prime untranslated regions of target messenger RNA (mRNA) transcripts, usually resulting in gene silencing. They were first discovered in 1993 by Victor Ambros, Rosalind Lee, and Rhonda Feinbaum during a study of the gene lin-14 in C. elegans development. These investigators found that LIN-14 protein abundance is regulated by a short RNA product encoded by the lin-4 gene. Retrospectively, the lin-4 small RNA was the first miRNA to be identified, though at the time it was thought to be a nematode idiosyncrasy. Not until 2000 was a second miRNA (let-7) characterized, which was found to be conserved in many species, indicating the existence of a wider phenomenon. The scientific committee session on myeloid biology today and tomorrow at 9:30 a.m. in Hall F1/F2 will illustrate how the miRNA phenomenon has spread to immune cell regulation, hematopoiesis, and cancer therapeutics.
In the first talk, Dr. Dinesh Rao of the University of California–Los Angeles will discuss how his laboratory identified miR-155 and miR-146a as targets of NF-κB, a transcription factor with a central role in inflammation and myeloid cell development. Interestingly, through gain- and loss-of-function experiments, these two miRNAs were found to play opposing roles in promoting immune cell and progenitor proliferation. The implications of these findings as they relate to NF-κB’s role in myeloid development will be addressed.
Dr. Curt Civin of the University of Maryland School of Medicine will then show how he was able to use global miRNA expression, mRNA expression, and miRNA–mRNA target predictions in human CD34+ hematopoietic stem-progenitor cells (HSPCs). Using these he formulated a model of hematopoietic differentation in which many genes specifying hematopoietic differentiation are expressed by early HSPCs but held in check by miRNAs. In addition, he will describe the tumor suppressive effects of the miR-23a cluster in acute leukemia and discuss efforts to expand miRNA profiling to more highly purified subsets of HSPCs.
Rounding out the session will be Dr. Judy Lieberman of Boston Children’s Hospital. She will provide an overview of miRNA dysregulation in cancer and how miRNA expression can affect prognosis and response to therapy. Because miRNAs regulate cancer cell differentiation, proliferation, survival, and metastasis, manipulating miRNA function could provide a powerful therapeutic strategy to interfere with key pathways for cancer progression. Her talk will explore some of the opportunities for and obstacles to harnessing miRNA biology for cancer therapy.
How remarkable that only 10 years after the initial discovery of a single miRNA in mammals, we now know of several hundred, many of which are viable therapeutic targets in malignancy. Given the magnitude of these findings, it is absolutely crucial that credit be given where it is due (sorry Mickey, it’s not the mouse). Thank you C.elegans!
Dr. Mendler indicated no relevant conflicts of interest.