Interleukin-7 receptor α (IL7R) is required for normal lymphoid development. Loss-offunction 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. © 2011 by The Rockefeller University Press.

Shochat, C., Tal, N., Bandapalli, O., Palmi, C., Ganmore, I., Te Kronnie, G., et al. (2011). Gain-of-function mutations in interleukin-7 receptor-{alpha} (IL7R) in childhood acute lymphoblastic leukemias. JOURNAL OF EXPERIMENTAL MEDICINE, 208(5), 901-908 [10.1084/jem.20110580].

Gain-of-function mutations in interleukin-7 receptor-{alpha} (IL7R) in childhood acute lymphoblastic leukemias

PALMI, CHIARA;Cazzaniga, G;BIONDI, ANDREA;
2011

Abstract

Interleukin-7 receptor α (IL7R) is required for normal lymphoid development. Loss-offunction 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. © 2011 by The Rockefeller University Press.
Articolo in rivista - Articolo scientifico
IL7 receptor, Childhood ALL
English
2011
208
5
901
908
none
Shochat, C., Tal, N., Bandapalli, O., Palmi, C., Ganmore, I., Te Kronnie, G., et al. (2011). Gain-of-function mutations in interleukin-7 receptor-{alpha} (IL7R) in childhood acute lymphoblastic leukemias. JOURNAL OF EXPERIMENTAL MEDICINE, 208(5), 901-908 [10.1084/jem.20110580].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/21747
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