Thompson Scott B, Wigton Eric J, Krovi Sai Harsha, Chung Jeffrey W, Long Robert A, Jacobelli Jordan
Department of Biomedical Research, National Jewish Health, Denver, CO, United States.
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States.
Front Oncol. 2018 Sep 20;8:389. doi: 10.3389/fonc.2018.00389. eCollection 2018.
Leukemias typically arise in the bone marrow and then spread to the blood and into other tissues. To disseminate into tissues, leukemia cells migrate into the blood stream and then exit the circulation by migrating across vascular endothelial barriers. Formin proteins regulate cytoskeletal remodeling and cell migration of normal and malignant cells. The Formin mDia1 is highly expressed in transformed lymphocytes and regulates lymphocyte migration. However, the role of mDia1 in regulating leukemia progression is unknown. Here, we investigated how mDia1 mediates the ability of leukemia cells to migrate and disseminate . For these studies, we used a mouse model of Bcr-Abl pre-B cell acute lymphoblastic leukemia. Our data showed that mDia1-deficient leukemia cells have reduced chemotaxis and ability to complete transendothelial migration . , mDia1 deficiency reduced the ability of leukemia cells to engraft in recipient mice. Furthermore, leukemia dissemination to various tissues and leukemia progression were inhibited by mDia1 depletion. Finally, mDia1 depletion in leukemia cells resulted in prolonged survival of recipient mice in a leukemia transfer model. Overall, our data show that the Formin mDia1 mediates leukemia cell migration, and drives leukemia engraftment and progression , suggesting that targeting mDia1 could provide a new method for treatment of leukemia.
白血病通常起源于骨髓，然后扩散到血液及其他组织。为了扩散到组织中，白血病细胞迁移到血流中，然后通过跨越血管内皮屏障而离开循环系统。formin蛋白调节正常细胞和恶性细胞的细胞骨架重塑及细胞迁移。formin蛋白mDia1在转化的淋巴细胞中高度表达，并调节淋巴细胞迁移。然而，mDia1在调节白血病进展中的作用尚不清楚。在此，我们研究了mDia1如何介导白血病细胞迁移和扩散的能力。对于这些研究，我们使用了Bcr-Abl前B细胞急性淋巴细胞白血病的小鼠模型。我们的数据表明，缺乏mDia1的白血病细胞趋化性降低，完成跨内皮迁移的能力也降低。此外，mDia1缺陷降低了白血病细胞在受体小鼠体内植入的能力。此外，mDia1缺失抑制了白血病向各种组织的扩散及白血病进展。最后，在白血病细胞中耗尽mDia1导致白血病转移模型中受体小鼠的存活期延长。总体而言，我们的数据表明，formin蛋白mDia1介导白血病细胞迁移，并推动白血病植入和进展，这表明靶向mDia1可为白血病治疗提供一种新方法。
