Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
Blood. 2010 Feb 18;115(7):1385-93. doi: 10.1182/blood-2009-05-222166. Epub 2009 Dec 14.
The adapter protein Slp65 is a key component of the precursor-B (pre-B) cell receptor. Slp65-deficient mice spontaneously develop pre-B cell leukemia, but the mechanism by which Slp65(-/-) pre-B cells become malignant is unknown. Loss of Btk, a Tec-family kinase that cooperates with Slp65 as a tumor suppressor, synergizes with deregulation of the c-Myc oncogene during lymphoma formation. Here, we report that the presence of the immunoglobulin heavy chain transgene V(H)81X prevented tumor development in Btk(-/-)Slp65(-/-) mice. This finding paralleled the reported effect of a human immunoglobulin heavy chain transgene on lymphoma development in Emu-myc mice, expressing transgenic c-Myc. Because activation of c-Myc strongly selects for spontaneous inactivation of the p19(Arf)-Mdm2-p53 tumor suppressor pathway, we investigated whether disruption of this pathway is a common alteration in Slp65(-/-) pre-B cell tumors. We found that combined loss of Slp65 and p53 in mice transformed pre-B cells very efficiently. Aberrations in p19(Arf), Mdm2, or p53 expression were found in all Slp65(-/-) (n = 17) and Btk(-/-)Slp65(-/-) (n = 32) pre-B cell leukemias analyzed. In addition, 9 of 10 p53(-/-)Slp65(-/-) pre-B cell leukemias manifested significant Mdm2 protein expression. These data indicate that malignant transformation of Slp65(-/-) pre-B cells involves disruption of the p19(Arf)-Mdm2-p53 tumor suppressor pathway.
衔接蛋白 Slp65 是前 B 细胞受体的关键组成部分。Slp65 缺陷型小鼠自发发展为前 B 细胞白血病，但 Slp65(-/-)前 B 细胞恶变的机制尚不清楚。 Tec 家族激酶 Btk 的缺失，作为肿瘤抑制因子与 Slp65 协同作用，在淋巴瘤形成过程中与 c-Myc 癌基因的失调协同作用。在这里，我们报告免疫球蛋白重链转基因 V(H)81X 的存在可防止 Btk(-/-)Slp65(-/-)小鼠发生肿瘤。这一发现与 Emu-myc 小鼠中报道的人类免疫球蛋白重链转基因对淋巴瘤发展的影响相平行，这些小鼠表达转基因 c-Myc。由于 c-Myc 的激活强烈选择自发失活 p19(Arf)-Mdm2-p53 肿瘤抑制途径，我们研究了这种途径的破坏是否是 Slp65(-/-)前 B 细胞肿瘤的常见改变。我们发现，在小鼠中同时缺失 Slp65 和 p53 可非常有效地转化前 B 细胞。在所有分析的 Slp65(-/-)(n=17)和 Btk(-/-)Slp65(-/-)(n=32)前 B 细胞白血病中都发现了 p19(Arf)、Mdm2 或 p53 表达的异常。此外，在 10 个 p53(-/-)Slp65(-/-)前 B 细胞白血病中有 9 个表现出显著的 Mdm2 蛋白表达。这些数据表明，Slp65(-/-)前 B 细胞的恶性转化涉及 p19(Arf)-Mdm2-p53 肿瘤抑制途径的破坏。
