Department of Life Sciences, University of Siena, Siena
Department of Life Sciences, University of Siena, Siena.
Haematologica. 2019 Oct;104(10):2040-2052. doi: 10.3324/haematol.2018.209981. Epub 2019 Feb 28.
The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B-cell receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We analyzed the impact of p66Shc ablation on disease severity and progression in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. We showed that Eμ-TCL1/p66Shc mice developed an aggressive disease that had an earlier onset, occurred at a higher incidence and led to earlier death compared to that in Eμ-TCL1 mice. Eμ-TCL1/p66Shc mice displayed substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlated with upregulation of chemokine receptors whose ligands are expressed therein. This also applied to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to correlate inversely with these cells' level of p66Shc expression. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor ibrutinib. Our results highlight p66Shc deficiency as an important factor in the progression and severity of chronic lymphocytic leukemia and underscore p66Shc expression as a relevant therapeutic target.
Shc 家族衔接蛋白 p66Shc 作为 B 细胞受体触发的增殖和存活信号的负调节剂，通过增强活性氧的产生，促进依赖氧化应激的细胞凋亡。此外，p66Shc 控制调节淋巴细胞迁移的趋化因子受体的表达和功能。慢性淋巴细胞白血病细胞存在 p66Shc 表达缺陷，这有助于它们的延长存活，并与预后不良相关。我们分析了 p66Shc 缺失对慢性淋巴细胞白血病 Eμ-TCL1 小鼠模型疾病严重程度和进展的影响。我们表明，Eμ-TCL1/p66Shc 小鼠发展为侵袭性疾病，其发病更早、发生率更高且导致更早死亡，与 Eμ-TCL1 小鼠相比。Eμ-TCL1/p66Shc 小鼠在淋巴结和非淋巴结部位均有大量白血病细胞积聚。靶器官选择性与趋化因子受体的上调相关，趋化因子受体的配体在其中表达。这也适用于慢性淋巴细胞白血病细胞，其中趋化因子受体表达和器官浸润的程度与这些细胞的 p66Shc 表达水平呈负相关。在 Eμ-TCL1 小鼠中，p66Shc 的表达随着疾病的进展而下降，并且可以通过用 Bruton 酪氨酸激酶抑制剂 ibrutinib 治疗来恢复。我们的研究结果强调了 p66Shc 缺失是慢性淋巴细胞白血病进展和严重程度的重要因素，并强调了 p66Shc 表达作为一个相关的治疗靶点。
