Our published work includes a study of the intracellular domain of IL-7 receptor. This showed that the intracellular domain of other cytokine receptors can mimic some functions of the IL-7 receptor in T and B cell development. However one unique function of the IL-7 receptor is the induction of TCR gamma gene rearrangement. We also published our findings that pharmacological treatment with IL-7 induces a broad hematological stimulation, including myelopoiesis and erythropoiesis. This showed beneficial effects of IL-7 treatment beyond the expected effects on lymphopoiesis. We also published a study showing that signals from IL-7 receptor are required for development of T regulatory cells, and demonstrated that there is redundancy between the two ligands for IL-7R alpha TSLP and IL-7 itself. Although IL-7 is essential for normal T cell development and maintenance, it has not been determined which cells actually produce the IL-7 protein because it is below the level of detection by immunohistochemistry. We produced mice with a marker knocked into the IL-7 locus that permitted visualizing the producing cells. This showed an extensive reticular network of IL-7-containing processes in thymus and bone marrow and the study is submitted for publication. In collaboration with Rockland Inc., we produced a new antibody that is yielding new insights into signaling from the IL-7 receptor. This rabbit antibody reacts with the essential phosphotyrosine motif in the intracellular domain of IL-7 receptor. The prevailing model of signaling predicted that this motif would be phosphorylated after IL-7 stimulation, thereby attracting Stat5. However, we made the unanticipated observation that the site is constitutively phosphorylated and constitutively bound to Stat5. IL-7 stimulation therefore induces phosphorylation of Stat5, but not the IL-7 receptor as expected. This study is submitted for publication. We performed an extensive study of the roles of the death protein Bim and its counterpart, the pro-survival protein Mcl-1. We show that IL-7 regulates these proteins post-translationally and aim to define the mechanisms using an exciting new approach. IL-7 protects Mcl-1 from degradation and we have visualized this with Mcl-1-GFP. We are screening the whole expressed genome of shRNAs in lentivirus to identify components of this mechanism. This shRNA approach is an extremely powerful discovery tool in cancer research. To apply it to other systems in cancer cells, we submitted a proposal to the SBIR to offer a contract to array the entire human and mouse shRNA expressed genomes. The proposal was approved and this robotic screening method will be used by NCI to identify new pathways in cancer cells. Our collaborator J.Barata had characterized IL-7R in T-ALL patients. He identified insertions into IL-7R in the juxtamembrane region but had not found a functional consequence of these mutations. We showed that these mutant receptors were constitutively active, inducing phosphorylation of Jak1 and Stat5, that this induced survival and proliferation of an IL-7-dependent T cell line, and that this line formed tumors in mice. Thus IL-7R is an oncogene in T-ALL, which offers mechanistic explanations, and a therapeutic target using anti-IL-7R antibodies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC009287-27
Application #
8348929
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
27
Fiscal Year
2011
Total Cost
$588,703
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Cramer, Sarah D; Aplan, Peter D; Durum, Scott K (2016) Therapeutic targeting of IL-7R? signaling pathways in ALL treatment. Blood 128:473-8
Aprelikova, Olga; Tomlinson, Christine C; Hoenerhoff, Mark et al. (2016) Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases. PLoS One 11:e0155262
Andrews, Caroline; McLean, Mairi H; Durum, Scott K (2016) Interleukin-27 as a Novel Therapy for Inflammatory Bowel Disease: A Critical Review of the Literature. Inflamm Bowel Dis 22:2255-64
Robinette, Michelle L; Fuchs, Anja; Cortez, Victor S et al. (2015) Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat Immunol 16:306-17
Shen, Wei; Hixon, Julie A; McLean, Mairi H et al. (2015) IL-22-Expressing Murine Lymphocytes Display Plasticity and Pathogenicity in Reporter Mice. Front Immunol 6:662
Aiello, Francesca B; Graciotti, Laura; Procopio, Antonio D et al. (2013) Stemness of T cells and the hematopoietic stem cells: fate, memory, niche, cytokines. Cytokine Growth Factor Rev 24:485-501
Hasley, Rebecca B; Hong, Changwan; Li, Wenqing et al. (2013) HIV immune activation drives increased Eomes expression in memory CD8 T cells in association with transcriptional downregulation of CD127. AIDS 27:1867-77
Chen, Keqiang; Liu, Mingyong; Liu, Ying et al. (2013) Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis. J Clin Invest 123:1694-704
Patel, Ekta S; Okada, Starlyn; Hachey, Kevin et al. (2012) Regulation of in vitro human T cell development through interleukin-7 deprivation and anti-CD3 stimulation. BMC Immunol 13:46
Mazzucchelli, Renata I; Riva, Agostino; Durum, Scott K (2012) The human IL-7 receptor gene: deletions, polymorphisms and mutations. Semin Immunol 24:225-30

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