74 : IL-7R: Mutations in T-ALL and polymorphisms in autoimmunity
2013
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. 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 formed 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, γ c and Jak3-independent. Jak inhibitors were effective in blocking proliferation and survival of transformed cells. The hotspot for insertions lies in exon 6 in precisely the same region as a coding polymorphism regulating risk for MS and other autoimmune diseases, and we observe that this polymorphism affects strength of signaling. Our findings indicate that IL-7R mutations drive T-ALL, whereas polymorphisms that increase signaling promote autoimmunity, implicating IL-7R and Jak1 as therapeutic targets in these diseases.
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