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New mechanisms of resistance to chemotherapy among leukemia patients

March 19, 2016

With no chromosomal deletions, the microRNAs miR-15a and miR-16-1 inhibit expression of the tumor-suppressor TP53. However, TP53 in turn activates the two miRNAs, which then control expression of two other genes that prevent programmed cell death, or apoptosis. Apoptosis occurs at normal levels, preventing leukemia development.

TP53 also activates the miR34b and miR-34c microRNAs, which then inhibit the gene ZAP70, which is associated with shorter survival among CLL patients.

Why Indolent CLL Follows 13q Deletions

With 13q deletions, miR-15a and miR16-1 are reduced or absent, which allows for increased expression of TP53. This further activates miR-34b and miR-34a, resulting in greater inhibition of Zap70. That's the good part.

With miR-15a and 16-1 gone, expression of the two genes that suppress programmed cell death, BCL2 and MCL1, increases, which allows more aberrant cells to form and grow. While this effect causes slow-growing CLL, the counterweight of suppressed ZAP70 keeps it from getting worse, Calin said.

TP53 is, in effect, a link that joins the two different sets of microRNAs, the researchers noted.

Experiments in acute myeloid leukemia, lung and cervical cancer cell lines indicate the same mechanism may be at work in other cancer types, but more studies will be needed to validate that, Calin said.

This study clears the way for further translational research to identify microRNAs involved in resistance to CLL therapy and therefore poor outcomes for patients, as well as the identification of plasma miRNAs with predictive value for response to therapy. A team led by Calin and study co-author Michael Keating, M.D., professor in MD Anderson's Department of Leukemia, is investigating these topics.

SOURCE University of Texas MD Anderson Cancer Center