MicroRNAs targeting TCL1 as therapeutic agents for B-CLL
Yuri Pekarsky, Ph.D.
Ohio State University
Abstract:
B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, results from an expansion of a rare population of mature B-lymphocytes. In human B-CLL, expression of the TCL1 gene is abnormally increased in the aggressive form of B-CLL. This increased TCL1 expression in mice results in a disease similar to the aggressive form of human B-CLL. Our investigation of the function of TCL1 led to the discovery that TCL1 acts in the same pathway as Akt, a molecule that regulates several targets critical for malignant transformation of normal cells.
In our preliminary studies we determined that we can pass mouse B-CLL to other mice. Therefore we can treat the same B-CLL in a number of mice. This represents a good animal model to design and test drugs for this disease. We further investigated the regulation of TCL1 expression by microRNAs, small molecules that inhibit TCL1. We found that TCL1 is inhibited by two such molecules: miR-181 and miR-29. These molecules may be excellent candidates to use in the treatment of TCL1-driven B-CLL. Our goal is to establish microRNAs as therapeutic agents for B-CLL.
We hypothesize that these two microRNAs could be effective therapeutic agents to cure and/or prevent B-CLL. We propose to verify that miR-181 and miR-29 inhibit TCL1 protein expression and determine whether this effect is cumulative. We intend to produce a TCL1 transgenic mouse line specifically designed to treat B-CLL with miR-181 and miR-29. We will further determine if treatment with miR-181 and miR-29 prevents or cures transplanted B-CLL in these mice. Our experiments hope to establish microRNAs as novel therapeutic agents for B-CLL.
Useful Definition: TCL1: a human gene that is associated with the development of T-cell and B-cell leukemias and lymphomas MicroRNAs: small molecules that interfere with the ability of a gene to manufacture a protein. These molecules can regulate the expression of many genes and may play a role in establishing a treatment for B-CLL.