Department of Cancer Biology and Genetics and Comprehensive Cancer Center at the Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Department of Cancer Biology and Genetics and Comprehensive Cancer Center at the Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Adv Biol Regul. 2020 Jan;75:100669. doi: 10.1016/j.jbior.2019.100669. Epub 2019 Oct 13.
We established that loss of miR-15a/16-1 genes on chromosome 13q14 is the most common alteration in Chronic Lymphocytic Leukemia (CLL) and that miR-15/16 are crucial negative regulator of BCL-2, an antiapoptotic gene overexpressed in most CLLs and in many other malignancies. We have also shown that miR-15/16 target ROR1, a cell surface receptor for Wnt5a which can enhance growth/survival of CLL cells. Interestingly, ROR1 is expressed by many cancers, but not by normal adult tissues. Moreover, Venetoclax, the anti-Bcl-2 drug, and Cirmtuzumab, the monoclonal antibody against ROR1, are synergistic in killing CLL cells. Since an additional miR-15/16 locus exists on chromosome 3q25 (miR-15b/16-2), we generated a knocked out mouse model to study its the role in cancer. We observed that the KO mice developed predominantly CLL. Thus, we generated a double knock out mouse model where both miR-15/16 loci were deleted. Surprisingly we observed that 77% of double KO mice developed Acute Myeloid Leukemia (AML). Based on these evidences, we anticipate that also AMLs with low miR-15/16 expression, overexpression of BCL2 and expression of ROR1, would show an excellent response to a combination therapy with Venetoclax and Cirmtuzumab, since both drugs target the same malignant cells that have lost miR-15/16.
我们证实，13q14 染色体上 miR-15a/16-1 基因的缺失是慢性淋巴细胞白血病（CLL）最常见的改变，miR-15/16 是 BCL-2 的关键负调控因子，BCL-2 在大多数 CLL 中以及许多其他恶性肿瘤中过度表达。我们还表明，miR-15/16 的靶标是 ROR1，ROR1 是 Wnt5a 的细胞表面受体，它可以增强 CLL 细胞的生长/存活。有趣的是，ROR1 在许多癌症中表达，但在正常成人组织中不表达。此外，抗 Bcl-2 药物 Venetoclax 和针对 ROR1 的单克隆抗体 Cirmtuzumab 在杀死 CLL 细胞方面具有协同作用。由于 3q25 上还有另外一个 miR-15/16 基因座（miR-15b/16-2），我们生成了一个敲除小鼠模型来研究其在癌症中的作用。我们观察到 KO 小鼠主要发展为 CLL。因此，我们生成了一个双重敲除小鼠模型，其中两个 miR-15/16 基因座都被删除。令人惊讶的是，我们观察到 77%的双 KO 小鼠发展为急性髓系白血病（AML）。基于这些证据，我们预计 miR-15/16 表达低、BCL2 过表达和 ROR1 表达的 AML 也将对 Venetoclax 和 Cirmtuzumab 的联合治疗产生极好的反应，因为这两种药物都针对失去 miR-15/16 的相同恶性细胞。
