Kersseboom Rogier, Middendorp Sabine, Dingjan Gemma M, Dahlenborg Katarina, Reth Michael, Jumaa Hassan, Hendriks Rudolf W
Department of Immunology, Erasmus MC Rotterdam, PO Box 1738, NL-3000 DR Rotterdam, Netherlands.
J Exp Med. 2003 Jul 7;198(1):91-8. doi: 10.1084/jem.20030615. Epub 2003 Jun 30.
Expression of the pre-B cell receptor (pre-BCR) leads to activation of the adaptor molecule SLP-65 and the cytoplasmic kinase Btk. Mice deficient for one of these signaling proteins have an incomplete block in B cell development at the stage of large cycling pre-BCR+CD43+ pre-B cells. Our recent findings of defective SLP-65 expression in approximately 50% of childhood pre-B acute lymphoblastic leukemias and spontaneous pre-B cell lymphoma development in SLP-65-/- mice demonstrate that SLP-65 acts as a tumor suppressor. To investigate cooperation between Btk and SLP-65, we characterized the pre-B cell compartment in single and double mutant mice, and found that the two proteins have a synergistic role in the developmental progression of large cycling into small resting pre-B cells. We show that Btk/SLP-65 double mutant mice have a dramatically increased pre-B cell tumor incidence ( approximately 75% at 16 wk of age), as compared with SLP-65 single deficient mice (<10%). These findings demonstrate that Btk cooperates with SLP-65 as a tumor suppressor in pre-B cells. Furthermore, transgenic low-level expression of a constitutive active form of Btk, the E41K-Y223F mutant, prevented tumor formation in Btk/SLP-65 double mutant mice, indicating that constitutive active Btk can substitute for SLP-65 as a tumor suppressor.
前B细胞受体（pre-BCR）的表达会导致衔接分子SLP-65和细胞质激酶Btk的激活。缺乏这些信号蛋白之一的小鼠在大循环pre-BCR+CD43+前B细胞阶段的B细胞发育中存在不完全阻断。我们最近发现约50%的儿童前B急性淋巴细胞白血病中SLP-65表达缺陷，以及在SLP-65基因敲除小鼠中出现自发性前B细胞淋巴瘤，这表明SLP-65起到肿瘤抑制因子的作用。为了研究Btk与SLP-65之间的协同作用，我们对单突变和双突变小鼠的前B细胞区室进行了表征，发现这两种蛋白在大循环前B细胞向小静止前B细胞的发育进程中具有协同作用。我们发现，与SLP-65单基因缺陷小鼠（<10%）相比，Btk/SLP-65双突变小鼠的前B细胞肿瘤发生率显著增加（16周龄时约为75%）。这些发现表明，Btk在pre-B细胞中作为肿瘤抑制因子与SLP-65协同作用。此外，组成型活性形式的Btk即E41K-Y223F突变体的转基因低水平表达可预防Btk/SLP-65双突变小鼠中的肿瘤形成，这表明组成型活性Btk可替代SLP-65作为肿瘤抑制因子。
