Childhood Leukemia Research Institute and Department of Pediatric Hemato-Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
J Exp Med. 2011 May 9;208(5):901-8. doi: 10.1084/jem.20110580. Epub 2011 May 2.
Interleukin-7 receptor α (IL7R) is required for normal lymphoid development. Loss-of-function mutations in this gene cause autosomal recessive severe combined immune deficiency. Here, we describe somatic gain-of-function mutations in IL7R in pediatric B and T acute lymphoblastic leukemias. The mutations cause either a serine-to-cysteine substitution at amino acid 185 in the extracellular domain (4 patients) or in-frame insertions and deletions in the transmembrane domain (35 patients). In B cell precursor leukemias, the mutations were associated with the aberrant expression of cytokine receptor-like factor 2 (CRLF2), and the mutant IL-7R proteins formed a functional receptor with CRLF2 for thymic stromal lymphopoietin (TSLP). Biochemical and functional assays reveal that these IL7R mutations are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells. A cysteine, included in all but three of the mutated IL-7R alleles, is essential for the constitutive activation of the receptor. This is the first demonstration of gain-of-function mutations of IL7R. Our current and recent observations of mutations in IL7R and CRLF2, respectively suggest that the addition of cysteine to the juxtamembranous domains is a general mechanism for mutational activation of type I cytokine receptors in leukemia.
白细胞介素 7 受体 α（IL7R）是正常淋巴发育所必需的。该基因的功能丧失突变会导致常染色体隐性严重联合免疫缺陷。在这里，我们描述了儿科 B 和 T 急性淋巴细胞白血病中 IL7R 的体细胞获得性功能突变。这些突变导致细胞外结构域中丝氨酸到半胱氨酸的取代（4 名患者）或跨膜结构域中的框内插入和缺失（35 名患者）。在 B 细胞前体白血病中，这些突变与细胞因子受体样因子 2（CRLF2）的异常表达相关，突变的 IL-7R 蛋白与 CRLF2 形成功能性受体，用于胸腺基质淋 1 素（TSLP）。生化和功能测定表明，这些 IL7R 突变是激活突变，赋予祖细胞淋巴细胞的细胞因子非依赖性生长。除了三个突变的 IL-7R 等位基因外，所有的突变都包含一个半胱氨酸，该半胱氨酸对于受体的组成性激活是必需的。这是首次证明 IL7R 的获得性功能突变。我们目前和最近的观察结果表明，在 IL7R 和 CRLF2 中分别观察到的突变表明，在白血病中，将半胱氨酸添加到跨膜结构域的附近区域是 I 型细胞因子受体突变激活的一般机制。
