The IL-7 pathway is critical for regulating the number of lymphocytes as has been shown in humans as well as in mice. We and our collaborators recently showed that the IL-7 receptor is mutated in pediatric lymphocytic leukemia, and the mutant receptors drive cell division. We developed a panel of monoclonal antibodies against mutant receptors, all of which also react with normal receptors. These will be tested for activity against human leukemia cells transplanted into mice and the most promising will be evaluated for treating leukemia patients. Using a different approach, we showed that drugs which block signaling from IL-7 receptor are able to kill leukemia cells in vitro. These will be tested against human leukemia cells transplanted into mice and evaluated for treating patients. The same monoclonal antibodies and drugs will also be evaluated in autoimmune diseases. It was previously found by others that a polymorphism in the coding region of IL-7 receptor predisposes to autoimmune diseases. We recently found that this polymorphism regulates the strength of signal by the receptor, offering promise for inhibiting these signals in autoimmunity. Our group has studied the IL-7 pathway for a number of years and have published a number of papers on the subject. Most recently we, together with a number of collaborators, found activating mutations in the IL-7 receptor that drive lymphocytic leukemias (Zenatti et al, Nature Genetics 2011). We are developing therapeutics to treat patients who fail conventional chemotherapy. We also found that a polymorphism in IL-7 receptor regulates the strength of signal, and that high signaling predisposes to autoimmunity (Mazzucchelli et al Semin Immunol 2012). Therefore, antagonists of the IL-7 pathway may be effective in autoimmunity, and we are exploring this possibility. Relevant cancer sites: Non-Hodgkins Lymphoma, Leukemia. Relevant Research Areas: Immunology, Autoimmune Disease, Hematology/Lymph, Clinical Research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC009287-29
Application #
8763034
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2013
Total Cost
$636,846
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-7Rα signaling pathways in ALL treatment. Blood 128:473-8
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
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
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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
Mazzucchelli, Renata I; Riva, Agostino; Durum, Scott K (2012) The human IL-7 receptor gene: deletions, polymorphisms and mutations. Semin Immunol 24:225-30
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

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