Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
Department of Cancer Biology and Medical Genetics, The Ohio State University, Columbus, OH 43210.
Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10731-10736. doi: 10.1073/pnas.1708264114. Epub 2017 Sep 18.
Loss of is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of , 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 , which may target other drivers in CLL. We found that targets , 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 Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of may promote overexpression of , in addition to 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.
在慢性淋巴细胞白血病 (CLL) 中， 缺失是最常见的遗传病变，促进了 的过度表达， 参与了白血病的发病机制。事实上，Bcl2 的抑制剂 venetoclcax 在治疗 CLL 患者方面非常有效。然而，单独使用 venetoclcax 并不能在大多数患者中消除微小残留疾病。因此，我们对其他可能受 调节的基因感兴趣，这些基因可能是 CLL 的其他驱动因素。我们发现 靶向 ， 编码一种在超过 90%的 CLL 细胞上表达的癌胚表面蛋白，但在几乎所有正常产后组织中都不表达。高水平表达 ROR1 的 CLL 也高水平表达 Bcl2，但低至可忽略不计的 。此外，高水平 ROR1 的 CLL 病例比低至可忽略不计的 ROR1 的 CLL 病例更频繁地在染色体位置发生编码 （13q14）的基因缺失，这意味着除了 缺失外， 还可能促进 的过度表达。ROR1 是 Wnt5a 的受体，它可以促进白血病细胞的增殖和存活，并可以被 cirmtuzumab（一种人源化抗 ROR1 mAb）靶向。我们发现这种 mAb 可以增强高水平表达 ROR1 的 CLL 细胞中 venetoclcax 的体外细胞毒性活性，表明联合使用这些靶向 ROR1 和 Bcl2 的药物可能在患有这种疾病的患者中具有相加（如果不是协同）的活性。
