Venetian Institute of Molecular Medicine (VIMM), Centro di Eccellenza per la Ricerca Biomedica, Padua, Italy.
PLoS One. 2012;7(6):e39902. doi: 10.1371/journal.pone.0039902. Epub 2012 Jun 29.
In B-Chronic Lymphocytic Leukemia (B-CLL) kinase Lyn is overexpressed, active, abnormally distributed, and part of a cytosolic complex involving hematopoietic lineage cell-specific protein 1 (HS1). These aberrant properties of Lyn could partially explain leukemic cells' defective apoptosis, directly or through its substrates, for example, HS1 that has been associated to apoptosis in different cell types. To verify the hypothesis of HS1 involvement in Lyn-mediated leukemic cell survival, we investigated HS1 protein in 71 untreated B-CLL patients and 26 healthy controls. We found HS1 overexpressed in leukemic as compared to normal B lymphocytes (1.38±0.54 vs 0.86±0.29, p<0.01), and when HS1 levels were correlated to clinical parameters we found a higher expression of HS1 in poor-prognosis patients. Moreover, HS1 levels significantly decreased in ex vivo leukemic cells of patients responding to a fludarabine-containing regimen. We also observed that HS1 is partially localized in the nucleus of neoplastic B cells. All these data add new information on HS1 study, hypothesizing a pivotal role of HS1 in Lyn-mediated modulation of leukemic cells' survival and focusing, one more time, the attention on the BCR-Lyn axis as a putative target for new therapeutic strategies in this disorder.
在 B 慢性淋巴细胞白血病 (B-CLL) 中，Lyn 激酶过表达、激活、异常分布，并成为包含造血谱系细胞特异性蛋白 1 (HS1) 的细胞溶质复合物的一部分。Lyn 的这些异常特性部分可以解释白血病细胞的凋亡缺陷，直接或通过其底物（例如与不同细胞类型的凋亡相关的 HS1）来解释。为了验证 HS1 参与 Lyn 介导的白血病细胞存活的假说，我们在 71 例未经治疗的 B-CLL 患者和 26 例健康对照者中研究了 HS1 蛋白。我们发现与正常 B 淋巴细胞相比，白血病细胞中 HS1 过表达（1.38±0.54 比 0.86±0.29，p<0.01），并且当将 HS1 水平与临床参数相关联时，我们发现预后不良的患者 HS1 表达更高。此外，在对含氟达拉滨方案有反应的患者的体外白血病细胞中，HS1 水平显著降低。我们还观察到 HS1 部分定位于肿瘤性 B 细胞的核内。所有这些数据增加了对 HS1 研究的新信息，假设 HS1 在 Lyn 介导的白血病细胞存活调节中起关键作用，并再次将 BCR-Lyn 轴作为该疾病新治疗策略的潜在靶点。
