IL-7R: a target in ALL and autoimmunity — ASN Events

IL-7R: a target in ALL and autoimmunity (#245)

Scott Durum 1 , W. Q. Li 1 , E. Senkevitch 1 , P. Zenatti 2 , D. Ribeiro 3 , L. Zuurbier 4 , M. C. Silva 3 , M. Paganin 5 , J. Tritapoe 1 , J. A. Hixon 1 , A. B. Silveira 2 , B. A. Cardoso 3 , L. M. Sarmento 3 , N. Correia 3 , M. L. Toribio 6 , J. Kobarg 7 , M. Horstmann 8 9 , R. Pieters 4 , S. R. Brandalise 2 10 , A. A. Ferrando 5 , J. P. Meijerink 4 , J. A. Yunes 2 11 , J. T. Barata 3
  1. National Cancer Institute, Frederick, MD, United States
  2. Centro Infantil Boldrini, Brazil
  3. Universidade de Lisboa, Portugal
  4. Erasmus Medical Center, The Netherlands
  5. Columbia University, USA
  6. Universidad Autónoma de Madrid, Spain
  7. Centro Nacional de Pesquisa em Energia e Materiais, Brazil
  8. German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia, Germany
  9. University Medical Center Hamburg-Eppendorf, Germany
  10. Universidade Estadual de Campinas, Brazil
  11. Universidade Estadual de Campinas, Brazil

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. Constitutive signaling required homodimerization via cysteines in the inserted sequences and downstream Jak1 activation, and was IL-7, gc and Jak3-independent. 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. Janus kinase inhibitors effectively killed these cells in vitro and in vivo.  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.