O023 Oncogenic IL-7R gain-of-function mutations in childhood T-ALL

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2012-09, Vol.59 (3), p.507-507
• Main Authors: Durum, S., Li, W., Zenatti, P., Ribeiro, D., Zuurbier, L., Silva, M., Paganin, M., Tritapoe, J., Hixon, J., Silveira, A., Cardoso, B., Sarmento, L., Correia, N., Toribio, M., Kobarg, J., Horstmann, M., Pieters, R., Brandalise, S., Ferrando, A., Meijerink, J., Yunes, J., Barata, J.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute lymphatic leukemia; Amino acids; Bone marrow; Cell survival; Children; Cysteine; Development; Homeostasis; Interleukin 7; Janus kinase; Leukemogenesis; Liver; Lymph nodes; Lymphocytes T; Malignancy; Metastases; Mutation; Pediatrics; Proline; Signal transduction; Spleen; Stem cells; Thymus; Transformation; Tumors
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2012.06.055

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy resulting from leukemic transformation of T-cell progenitors in the thymus. It accounts for approximately 15% of ALL cases in childhood and 20–25% in adults and is a leading cause of death in children. IL-7 and its receptor (IL-7R) play a critical role in normal T-cell development and homeostasis. The IL-7R gene was sequenced in T-ALL from three cohorts. Mutations in IL-7R were identified in 9% of pediatric T-ALL patients. These mutations usually involved insertions of three amino acids including cysteine and proline in the extracellular juxtamembrane region. WT or mutant forms of the human IL-7R (hIL-7R) from patients were retrovirally transfected into an IL-7-dependent murine thymic cell line D1. Mutant hIL-7Rs induced ligand-independent activation of the Jak-Stat and PI3K pathways, cell survival and proliferation. Notably, mutant hIL-7R-expressing D1 cells induced subcutaneous tumors in Rag1-/- mice, with substantial infiltration into various organs that are normally affected in advanced stages of T-ALL, such as bone marrow, liver, lymph nodes and spleen. Further functional assays revealed that mutant hIL-7Rs constitutive signaling required homodimerization via cysteines in the inserted sequences and downstream Jak1 activation, and was IL-7, gc and Jak3-independent. Our findings indicate that hIL-7R mutational activation drives T-ALL leukemogenesis and implicate IL-7R and Jak1 as therapeutic targets in T-ALL.