Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) accounts for 7- 8% of all non-Hodgkin lymphomas. This tumor arises in sites that are normally devoid of lymphoid tissue, but which acquire organized lymphoid tissue as a result of chronic inflammation prior to the onset of lymphoma. The recurrent chromosomal translocation t(11;18)(q21;q21) occurs in up to 40% of cases and is associated with treatment resistance and tendency to disseminate. This translocation results in the creation of a chimeric protein composed of amino terminal sequences of Inhibitor of Apoptosis 2 (API2) fused to carboxy terminal sequences of MALT1. Despite strong evidence for an important role for t(11;18) in MALT lymphomagenesis, the molecular mechanisms underlying API2-MALT1's oncogenic activity have not been defined. The studies described in this proposal are aimed at elucidating the role of the API2 moiety in API2-MALT1-dependent oncogenic activity. We hypothesize that the API2 moiety of API2-MALT1 contributes to oncogenesis by mediating oligomerization of the fusion protein and by interacting with critical signaling proteins that regulate cell survival. We will use a combination of biochemical studies, cellular transformation analyses and mouse models to test this hypothesis. This research will further our understanding of the complex relationship between inflammation and cancer. The anticipated results will provide significant insight into the molecular pathogenesis of MALT lymphoma and will pave the way toward the development of novel rational therapies for refractory disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124540-05
Application #
8306141
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Howcroft, Thomas K
Project Start
2008-09-01
Project End
2012-11-30
Budget Start
2012-08-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$151,437
Indirect Cost
$53,802
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Rosebeck, S; Rehman, A O; Apel, I J et al. (2014) The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-?B signaling. Oncogene 33:2520-30
McAllister-Lucas, Linda M; Baens, Mathijs; Lucas, Peter C (2011) MALT1 protease: a new therapeutic target in B lymphoma and beyond? Clin Cancer Res 17:6623-31
Rosebeck, Shaun; Madden, Lisa; Jin, Xiaohong et al. (2011) Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 331:468-72
Rosebeck, Shaun; Rehman, Aasia O; Lucas, Peter C et al. (2011) From MALT lymphoma to the CBM signalosome: three decades of discovery. Cell Cycle 10:2485-96
Rosebeck, Shaun; Lucas, Peter C; McAllister-Lucas, Linda M (2011) Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment. Future Oncol 7:613-7