Division of Hematology, The Ohio State University, Columbus, Ohio.
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
Clin Cancer Res. 2019 Oct 15;25(20):6260-6273. doi: 10.1158/1078-0432.CCR-19-0273. Epub 2019 Jul 11.
Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL.
We crossed the Eμ-TCL1 mouse model with the Eμ-Myc mouse model to investigate the clinical phenotype associated with B-cell-restricted expression of these oncogenes. The resulting malignancy was then extensively characterized, from both a clinical and biologic perspective.
Eμ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically, immunophenotypically, and molecularly distinct concurrent CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in the double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was, however, observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma.
The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL.
异常表达 Myc 是侵袭性淋巴瘤发病机制中的一个主要因素，这些淋巴瘤虽然临床表现存在异质性，但往往对目前可用的治疗方法具有耐药性，且生存率较差。在 CLL 背景下观察到的侵袭性淋巴瘤中也可以看到 Myc 的表达，我们试图开发一种可用于研究 CLL 背景下侵袭性淋巴瘤治疗策略的小鼠模型。
我们将 Eμ-TCL1 小鼠模型与 Eμ-Myc 小鼠模型进行杂交，以研究这些致癌基因在 B 细胞受限表达时相关的临床表型。然后从临床和生物学两个角度对由此产生的恶性肿瘤进行了广泛的特征描述。
Eμ-TCL1xMyc 小鼠均匀地发展为具有高度侵袭性的淋巴样疾病，具有组织学、免疫表型和分子上明显不同的同时存在的 CLL 和 B 细胞淋巴瘤，导致寿命明显缩短。将来自患病 Eμ-TCL1xMyc 的细胞注入 WT 小鼠中，可建立类似于双转基因小鼠的疾病。患病的 Eμ-TCL1xMyc 小鼠和经过继转移后发病的小鼠均不能对伊布替尼产生反应。然而，通过使用一种目前正在开发用于复发/难治性恶性肿瘤（包括 CLL 和淋巴瘤）的核输出蛋白 exportin-1（XPO1）的选择性抑制剂，可有效地、持久地控制疾病。
Eμ-TCL1xMyc 小鼠是一种新的侵袭性 B 细胞淋巴瘤的临床前工具，包括在 CLL 背景下。
