<i>MicroRNA</i> dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia.

Abstract

Loss of <i>miR-15/16</i> is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of <i>BCL2</i>, which factors in leukemia pathogenesis. Indeed, an inhibitor of Bcl2, venetoclcax, is highly active in the treatment of patients with CLL. However, single-agent venetoclcax fails to eradicate minimal residual disease in most patients. Accordingly, we were interested in other genes that may be regulated by <i>miR-15/16</i>, which may target other drivers in CLL. We found that <i>miR-15/16</i> targets <i>ROR1</i>, which encodes an onco-embryonic surface protein expressed on the CLL cells of over 90% of patients, but not on virtually all normal postpartum tissues. CLL with high-level expression of ROR1 also have high-level expression of Bcl2, but low-to-negligible <i>miR-15/16</i> Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding <i>miR-15/16</i> (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of <i>miR-15/16</i> may promote overexpression of <i>ROR1</i>, in addition to <i>BCL2</i> ROR1 is a receptor for Wnt5a, which can promote leukemia-cell proliferation and survival, and can be targeted by cirmtuzumab, a humanized anti-ROR1 mAb. We find that this mAb can enhance the in vitro cytotoxic activity of venetoclcax for CLL cells with high-level expression of ROR1, indicating that combining these agents, which target ROR1 and Bcl2, may have additive, if not synergistic, activity in patients with this disease.