title: Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias.
abstract: 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.
authors.affiliation: Childhood Leukemia Research Institute and Department of Pediatric Hemato-Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Shochat
authors.forename: Noa
authors.initials: N
authors.lastname: Tal
authors.forename: Obul R
authors.initials: OR
authors.lastname: Bandapalli
authors.forename: Chiara
authors.initials: C
authors.lastname: Palmi
authors.forename: Ithamar
authors.initials: I
authors.lastname: Ganmore
authors.forename: Geertruy
authors.initials: G
authors.lastname: te Kronnie
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D054503:Lymphoid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: C498762:CRLF2 protein, human; D016207:Cytokines; D018121:Receptors, Cytokine; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000094632:Thymic Stromal Lymphopoietin