George Adrian Calin. M.D., Ph.D. University of Texas MD Anderson Cancer Center

GENETICS

Roles of microRNA in familial chronic lymphocytic leukemia

Grant awarded in 2006

Abstract:

The way in which CLL cells are initiated and develop into a life-threatening disease makes B-cell chronic lymphocytic leukemia (B-CLL) an enigma. Other family members of CLL patients also develop CLL or other types of cancer much more frequently than expected by chance. We propose that the responsible genes, at least for a portion of the patients, are genes recently identified and named microRNAs (miRNAs). These are very small genes (about 20 to 22 nucleotides) that do not codify for proteins but interact and degrade the messenger of the protein coding genes. Previously, we reported that mir-15a and mir-16-1 are located at chromosome 13q14, a region deleted in >50% of sporadic and familial B-CLLs and that a germline mutation in mir-16-1 gene is influencing the transcription levels of this gene.

To achieve our goal we will use a panel of 50 to 100 familial CLLs and the available family members from the CLL consortium registry. We will analyze the expression of miRNAs in familial cases versus non-familial cancers and versus normal hematopoietic cells using a microarray technology that we developed. We will also screen for the presence of alterations in the DNA sequence of microRNAs in malignant and normal cells from CLL patients. The endpoint of the first year will be to be able to identify microRNAs that, when altered, can cause the familial form of CLL. In the next step we will use computer-assisted research and various experimental approaches to determine the way in which these miRNAs act on different targets and the cellular mechanisms that are altered. We will create a list of possible molecules with important therapeutic implications.