Noncoding RNA genes in cancer pathogenesis.

By using chronic lymphocytic leukemia as target for discovery in cancer pathogenesis we discovered that the great majority of CLLs (75-85%) carry a deletion of miR-15a and miR-16-1 at 13q14. We also discovered that miR-15/16 are negative regulators of the BCL2 oncogene. Thus the loss of the two negative regulators causes BCL2 overexpression and leukemia. A corollary of this is that CLL is very sensitive to the anti BCL2 drug venetoclax that can induce complete remission in CLL patients. Since leukemia patients may carry billions of leukemia cells, it is quite likely that some (few) of the leukemic cells are resistant to venetoclax. Thus, since microRNAs have multiple targets, we looked for other proteins that may be overexpressed in CLL because of the low of miR-15/16. We discovered that ROR1 an embryonal antigen expressed on most (∼ 90%) CLL, but not on normal B cell, is also regulated by miR-15/16. Thus CLL cells are also sensitive to monoclonal antibodies against ROR1. Venetoclax and monoclonal antibodies against ROR1 act synergistically in killing CLL cells.