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MiRNA Fingerprint Identified in Platelet Formation

17.03.2006

Scientists have identified a handful of microRNAs (miRNAs) that appear to play a significant role in the development of platelets – blood cells critical to the body’s ability to form clots following an injury. They also say some of these same miRNAs, when acting abnormally, may contribute to certain forms of leukemia.

“Basically, we found that a specific set of miRNA genes are turned off in normal platelet development, but turned on in certain platelet-related leukemia cells,” says lead author Dr. Ramiro Garzon, a clinical instructor in The Ohio State University College of Medicine.

The study is published online in the Proceedings of the National Academy of Sciences.

MiRNA has only recently been acknowledged as an important force in biology. For decades, scientific dogma has held that messenger RNA (mRNA) was responsible for carrying out DNA instructions, or code, for protein production in the cell. Little was known, however, about how cells actually regulated that process. But over the past 10 years, researchers have discovered that miRNA – tiny fragments of RNA typically no more than 20-25 nucleotides in length – also regulates protein synthesis by interfering with mRNA’s original instructions. They now know that miRNA helps to regulate many key biological processes, including cell growth, death, development and differentiation.

Dr. Carlo Croce, director of Ohio State’s Human Cancer Genetics Program, was the first to discover a link between miRNA and cancer. In the current study, Croce, who is also a member of the OSU Comprehensive Cancer Center, along with Garzon and colleagues from the M.D. Anderson Cancer Center, examined miRNA activity in the earliest phases of platelet development.

The researchers had previously uncovered substantial evidence linking certain patterns of miRNA to both normal and abnormal blood cell development, especially in diseases like chronic lymphocytic leukemia and lymphoma. Relatively little was known, however, about miRNA functionality in platelet formation.

Platelets are created from stem cells in the bone marrow. They evolve through a process called megakaryocytopoiesis, which generates megakaryocytes, or platelet parent cells.

The research team used microRNA gene chip analysis to identify miRNA expression in normal stem cells and megakaryoctyes. They also studied miRNA expression patterns in four acute megakaryoblastic leukemia (AMKL) cell lines. They discovered that a set of 17 miRNAs are turned off during normal megakaryocyte differentiation and that 8 of those genes create a molecular signature that clearly defines a megakaryocyte from any other type of cell.

“We believe this set of genes may contribute to platelet formation,” says Garzon. “We think that when these miRNAs are turned off, it’s a signal to other gene targets to get busy with the normal process of development.” Garzon says just the opposite happens in AMKL, an unusual form of leukemia more often found in children than adults.

In examining four sets of AMKL lines, they found that 10 miRNAs were turned on, again representing a molecular signature for that disease. “Interestingly, half of that number are also members of the miRNA profile in normal platelet cell development – suggesting that this small subset may be most important in understanding how AMKL develops, says Garzon.

Researchers believe that more knowledge about miRNA could lead to a new class of targeted therapies that may be helpful in treating leukemia and other diseases. “That day, however, is still a long way off,” says Garzon.

Grants from the National Cancer Institute, the Leukemia & Lymphoma Society, the Kimmel Foundation and a CLL Research Foundation Grant helped support the study.

Additional co-authors from OSU’s department of molecular virology, immunology and medical genetics include Flavia Pichiorri, Tizaiana Palumbo, Rodolfo Iuliano, Amelia Cimmino, Rami Aqeilan, Stefano Volinia, Darshna Bhatt, Hansjuerg Alder, Guido Marcucci, George Calin, Chang-Gong Liu and Clara Bloomfield. Michael Andreeff, who also helped with the study, is from the M.D. Anderson Cancer Center.