MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia.

Abstract

Loss of miR-15/16 is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of BCL2, 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 miR-15/16, which may target other drivers in CLL. We found that miR-15/16 targets ROR1, 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 miR-15/16 Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding miR-15/16 (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of miR-15/16 may promote overexpression of ROR1, in addition to BCL2 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.

• Authors: Laura Z Rassenti, Veronica Balatti, Emanuela M Ghia, Alexey Palamarchuk, Luisa Tomasello, Paolo Fadda, Yuri Pekarsky, George F Widhopf 2nd, Thomas J Kipps, Carlo M Croce
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 40 Pg. 10731-10736 (10 03 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28923920 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• BCL2 protein, human
• Biomarkers, Tumor
• Bridged Bicyclo Compounds, Heterocyclic
• MIRN15 microRNA, human
• MIRN16 microRNA, human
• MicroRNAs
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors
• venetoclax

Topics

• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cohort Studies
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics, pathology)
• MicroRNAs (genetics)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Receptor Tyrosine Kinase-like Orphan Receptors (antagonists & inhibitors, genetics, immunology, metabolism)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured