Multiple Roles of the API2 Moiety in API2-MALT1-Mediated Lymphomagenesis

Summary

Principal Investigator: LINDA MCALLISTER LUCAS
Affiliation: University of Michigan
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: ----------------2008 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. doi Finally, MALT1 is a protease!
    Linda M McAllister-Lucas
    Nat Immunol 9:231-3. 2008
  2. ncbi The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling
    S Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
    Oncogene 33:2520-30. 2014
  3. pmc Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation
    Shaun Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
    Science 331:468-72. 2011
  4. pmc Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment
    Shaun Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
    Future Oncol 7:613-7. 2011
  5. pmc From MALT lymphoma to the CBM signalosome: three decades of discovery
    Shaun Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA
    Cell Cycle 10:2485-96. 2011
  6. pmc MALT1 protease: a new therapeutic target in B lymphoma and beyond?
    Linda M McAllister-Lucas
    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA
    Clin Cancer Res 17:6623-31. 2011

Scientific Experts

  • LINDA MCALLISTER LUCAS
  • Linda M McAllister-Lucas
  • Shaun Rosebeck
  • Peter C Lucas
  • S Rosebeck
  • Mathijs Baens
  • M Q Du
  • A O Rehman
  • A T Ting
  • A Appert
  • M Baens
  • M A O'Donnell
  • L M McAllister-Lucas
  • P C Lucas
  • D Kohrt
  • I J Apel
  • Alex Appert
  • Xavier Sagaert
  • Aasia O Rehman
  • Shufang Gu
  • Heidi Noels
  • Ingrid J Apel
  • Ming Qing Du
  • Xiaohong Jin
  • Rifat A Hamoudi
  • Lisa Madden
  • Peter Van Loo

Detail Information

Publications6

  1. doi Finally, MALT1 is a protease!
    Linda M McAllister-Lucas
    Nat Immunol 9:231-3. 2008
  2. ncbi The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling
    S Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
    Oncogene 33:2520-30. 2014
    ..Intriguingly, constitutive RIP1 ubiquitination was recently demonstrated in several solid tumors, and now our study implicates RIP1 ubiquitination as a critical component of API2-MALT1-dependent lymphomagenesis. ..
  3. pmc Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation
    Shaun Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
    Science 331:468-72. 2011
    ..Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease...
  4. pmc Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment
    Shaun Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
    Future Oncol 7:613-7. 2011
    ....
  5. pmc From MALT lymphoma to the CBM signalosome: three decades of discovery
    Shaun Rosebeck
    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA
    Cell Cycle 10:2485-96. 2011
    ..CBM signalosome activity is important for normal cellular functions and is perturbed in neoplastic and inflammatory disorders, making it a viable target for novel therapeutic design...
  6. pmc MALT1 protease: a new therapeutic target in B lymphoma and beyond?
    Linda M McAllister-Lucas
    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA
    Clin Cancer Res 17:6623-31. 2011
    ....