Shukla Ashima, Cutucache Christine E, Sutton Garrett L, Pitner Michael A, Rai Karan, Rai Siddharth, Opavsky Rene, Swanson Patrick C, Joshi Shantaram S
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE.
Department of Biology, University of Nebraska, Omaha, NE.
Exp Hematol. 2016 Jan;44(1):30-7.e1. doi: 10.1016/j.exphem.2015.09.005. Epub 2015 Oct 3.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. The tissue microenvironment, specifically the lymph nodes, influences the biological and clinical behavior of CLL cells. Gene expression profiling of CLL cells from peripheral blood, bone marrow, and lymph nodes revealed Cav-1 as one of the genes that might be involved in the pathogenesis of CLL. We have previously reported that the knockdown of Cav-1 in primary CLL cells exhibits a significant decrease in cell migration and immune synapse formation. However, the precise role of Cav-1 in CLL initiation and progression in vivo is not known. Therefore, we decreased the expression of Cav-1 in vivo by breeding Eμ-TCL1 with cav-1 knockout mice. We observed a significant decrease in the number of CLL cells and rate of proliferation of CLL cells in spleen, liver, and bone marrow from Eμ-TCL1-Cav1(-/+) and Eμ-TCL1-Cav1(-/-) mice as compared with Eμ-TCL1 mice. In addition, there was a significant increase in survival of Eμ-TCL1-Cav1(-/+) and Eμ-TCL1-Cav1(-/-) compared with Eμ-TCL1 mice. Mechanistically, we observed a decrease in MAPK-Erk signaling measured by p-Erk levels in Eμ-TCL1-Cav1(-/+) mice when compared with Eμ-TCL1-Cav(wt/wt). Together these results indicate that decreased Cav-1 in Eμ-TCL1 mice significantly delays the onset of CLL and decreases leukemic progression by inhibiting MAPK-Erk signaling, suggesting a role for Cav-1 in the proliferation and progression of CLL.
慢性淋巴细胞白血病（CLL）是美国最常见的成人白血病。组织微环境，特别是淋巴结，会影响CLL细胞的生物学和临床行为。对来自外周血、骨髓和淋巴结的CLL细胞进行基因表达谱分析发现，Cav-1是可能参与CLL发病机制的基因之一。我们之前报道过，在原发性CLL细胞中敲低Cav-1会使细胞迁移和免疫突触形成显著减少。然而，Cav-1在CLL体内起始和进展过程中的精确作用尚不清楚。因此，我们通过将Eμ-TCL1与cav-1基因敲除小鼠杂交，在体内降低了Cav-1的表达。我们观察到，与Eμ-TCL1小鼠相比，Eμ-TCL1-Cav1（- / +）和Eμ-TCL1-Cav1（- / -）小鼠脾脏、肝脏和骨髓中的CLL细胞数量显著减少，CLL细胞增殖速率降低。此外，与Eμ-TCL1小鼠相比，Eμ-TCL1-Cav1（- / +）和Eμ-TCL1-Cav1（- / -）小鼠的生存期显著延长。从机制上讲，与Eμ-TCL1-Cav（wt / wt）相比，我们观察到Eμ-TCL1-Cav1（- / +）小鼠中通过p-Erk水平测量的MAPK-Erk信号传导减少。这些结果共同表明，Eμ-TCL1小鼠中Cav-1的减少通过抑制MAPK-Erk信号传导显著延迟了CLL的发病并降低了白血病进展，提示Cav-1在CLL增殖和进展中发挥作用。
