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Publications

Calin and Zenz - DKFZ/MD Anderson SINF Awardees

Deciphering the role of non-coding RNA in chronic lymphocytic leukemia (CLL)

George Calin and Thorsten Zenz (DKFZ), along with Martina Seiffert, Peter Lichter, Daniel Mertens, Rainer Claus, Christoph Plass, Axel Benner, and Hanno Glimm (DKFZ)

George Calin, M.D., Ph.D., is a rebel. Not in the sense of a 1950s, motorcycle-riding, cigarette-smoking, going-wherever-the-road-takes-you rebel, but as an individual and a scientist seeking answers. He rebels against the notion of an aloof physician-scientist who feels he is wasting his time with anyone who is not also a physician-scientist. He rebels against the idea that one must always be staunch and serious and he rebels against the idea that cancer cannot actually be cured. According to Calin, at least part of the solution to the latter lies in expanded understanding of non-coding ribonucleic acid (ncRNA).

Non-coding RNAs are functional genes but do not code for a protein, an idea which was considered a heresy initially by many scientists, because the general assumption had been that proteins are the primary, functional product of genetic information. Research over the past decade has shown the majority of mammalian genomes are also transcribed into ncRNAs. Many of these ncRNAs and their smaller products, do contain information and have a function, although the majority of those functions remain unknown. The deletion of two of those smaller products, micro RNAs (miRNA) 15a and 16-1, have been shown by Calin and colleagues to cause chronic lymphocytic leukemia (CLL), the most frequent form of adult leukemia in humans. Regulators of gene expression, miRNAs expressed abnormally in tumors can either contribute to oncogenesis or to suppression. Calin was the first scientist to illustrate the connection between miRNA and cancer in humans.

Calin’s DKFZ colleague, Thorsten Zenz, M.D., Ph.D., shares the desire to improve cancer patient care and treatment and has spent his career trying to do so for those with CLL. Zenz’s group has contributed to the understanding of the mechanisms underlying CLL and how that structure affects treatment and ultimately care. His group illustrated that defects in the tumor suppressor protein p53 can lead to both CLL and treatment-resistant CLL, known as refractory. Zenz’s group contributed to the research body illustrating 17p deletion, a chromosome on the tumor protein 53 gene (TP53), leads to CLL resistant to chemotherapy. Even with their genetic understanding of CLL, however, Zenz’s group showed physicians can only predict about half of the cases that will become refractory. He wants to know what is causing the other half.

Zenz and Calin think ncRNAs and miRNAs are at least part of the cause and want to determine which of these associated with p53 result in CLL and refractory CLL. But they do not believe the ncRNAs will account for all the unaccounted p53 resultant CLL. Therefore, they also hope to determine other mechanisms not associated with p53 that are leading to CLL. Coming full-circle back to the patient, the research project aims to show, in a clinical setting, the impact of the deregulated ncRNA on CLL and Richter transformation, which occurs when CLL changes to fast-growing, diffuse large B cell lymphoma (DLBL). By accounting for these knowledge gaps, Zenz and Calin hope to define predictive biomarkers, thereby allowing physicians to make better decisions about treatment.

 


© 2014 The University of Texas MD Anderson Cancer Center