The acute lymphoid leukemias (ALL) are widely associated with chromosomal abnormalities and recurrent genetic mutations. A recent study describes the occurrence of mutations in exon 6 of the IL-7 receptor (IL7Ra) alpha chain gene in 9% of the T phenotype ALL (ALL-T). In most cases (80%), IL7Ra mutations resulted in insertion of a cysteine in the extracellular portion juxtaposed to the transmembrane receptor domain. The "mutant" cysteine contributes to the unusual formation of homodimers/oligomers of IL7Ra, constitutive signaling via JAK1/STAT5 and induction of cell survival and proliferation, typical of oncogenic mutations. The present project aims to better detail the mechanism of dimerization and subcellular localization of mutant IL7R signaling. Effect of cystein mutagenesis (insertions and deletions) on IL7R dimers/oligomers formation and signaling strength will be analyzed. Since homodimers/oligomers can be formed already in the endoplasmic reticulum, attempts will be made to better describe the IL7R dimerization/oligomerization in this cell compartment. A better understanding of the structure and function, of mutant IL-7R may help define ways of inhibiting its oncogenic action.
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