Extranodal marginal zone lymphomas of mucosa associated lymphoid tissue are one of the most common forms of non-Hodgkin lymphoma with steadily increasing incidence over the last two decades. The most common site of involvement is the stomach. Extranodal marginal zone lymphomas of the stomach (gastric MALT lymphomas) are associated with infection by the Helicobacter pylori organism in the vast majority of cases. The recognition of strong association of this disease with H. pylori and the dependence of the vast majority of the tumors on H. pylori antigen supported the revolutionary introduction of antibiotic regimens for the treatment of this form of cancer. In this regard, antibiotic eradication of the organism leads to regression of the gastric MALT lymphomas in up to 75% of cases. However, a subset of cases acquire a recurrent chromosomal translocation the t(11;18) which leads to the generation of an abnormal protein, the api2/MALT1 fusion that is important in the pathogenesis of this neoplasm. Importantly, api2/MALT1-positive lymphomas are unresponsive to antibiotic therapy and are characterized by a more aggressive clinical course. Currently, there are no known proteomic biomarkers for this antibiotic resistant form of gastric MALT lymphoma. Accordingly, in this application, we propose to utilize a suite of quantitative mass spectrometry-based proteomics strategies supported by sophisticated bioinformatics approaches to identify proteomic biomarkers of api2/MALT1 expressing MALT lymphomas.
In specific aim 1, we will perform global quantitative proteomic analysis in an unbiased fashion to identify the proteomic changes associated with expression of the api2/MALT1 fusion in mature human lymphoid cells.
In specific aim 2, we will develop a series of highly selective ion reaction monitoring strategies to detect api2/MALT1-positive lymphomas.
In specific aim 3, we will investigate the utility of the api2/MALT1 specific biomarkers for the detection of api2/MALT1 lymphomas in biopsy specimens, gastric juice and in plasma/serum samples.
In specific aim 4, we will make accessible and disseminate our raw and tandem mass spectrometry data for unrestricted interrogation by other groups. Our long-term goal is to identify robust, sensitive and specific biomarkers for the detection of the antibiotic-resistant api2/MALT1-positive form of extranodal marginal zone lymphoma. These studies have broad implications for the potential of quantitative mass spectrometry-based approaches for the identification of disease biomarkers for all forms of cancer.
The most common site affected by extranodal marginal zone B-cell lymphomas of mucosa associated lymphoid tissue is the stomach. This form of non-Hodgkin lymphoma is strongly and causally associated with the presence of a bacterial organism, Helicobacter pylori. In the majority of cases, antibiotic and antimicrobial therapy targeting the organism is an effective strategy for the treatment of this form of cancer. However, a subset of these gastric MALT lymphomas does not respond to antibiotic therapy and pursue an aggressive clinical course with adverse prognosis. The vast majority of these antibiotic resistant cases have been shown to harbor a chromosomal aberration which leads to the expression of an abnormal fusion protein known as api2-MALT1. There are no well-developed proteomic biomarkers for detection of this antibiotic resistant form of MALT lymphoma. Using sophisticated mass spectrometry strategies, we will identify the proteomic biomarkers of api2-MALT1-positive lymphomas. Our studies offer an opportunity for the early detection of antibiotic resistant gastric MALT lymphoma. The ability to routinely detect api2-MALT1-positive lymphoma with a minimally invasive approaches is a critical element in the overall strategy for the effective management and therapeutic monitoring of antibiotic resistant gastric MALT lymphoma.
|Sahasrabuddhe, A A; Chen, X; Chung, F et al. (2015) Oncogenic Y641 mutations in EZH2 prevent Jak2/Î²-TrCP-mediated degradation. Oncogene 34:445-54|
|Nie, Zilin; Du, Ming-Qing; McAllister-Lucas, Linda M et al. (2015) Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma. Nat Commun 6:5908|
|Kiel, Mark J; Sahasrabuddhe, Anagh A; Rolland, Delphine C M et al. (2015) Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in SÃ©zary syndrome. Nat Commun 6:8470|
|Sahasrabuddhe, Anagh A; Elenitoba-Johnson, Kojo S J (2015) The role of aberrant proteolysis in lymphomagenesis. Curr Opin Hematol 22:369-78|
|Sahasrabuddhe, Anagh A; Elenitoba-Johnson, Kojo S J (2015) Role of the ubiquitin proteasome system in hematologic malignancies. Immunol Rev 263:224-39|
|Chen, X; Sahasrabuddhe, A A; Szankasi, P et al. (2014) Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival. Cell Death Differ 21:1535-45|
|Chung, Fu-Zon; Sahasrabuddhe, Anagh A; Ma, Kaiyu et al. (2014) Fbxo45 inhibits calcium-sensitive proteolysis of N-cadherin and promotes neuronal differentiation. J Biol Chem 289:28448-59|
|Kiel, Mark J; Velusamy, Thirunavukkarasu; Rolland, Delphine et al. (2014) Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood 124:1460-72|
|Rolland, Delphine; Basrur, Venkatesha; Conlon, Kevin et al. (2014) Global phosphoproteomic profiling reveals distinct signatures in B-cell non-Hodgkin lymphomas. Am J Pathol 184:1331-42|
|Velusamy, Thirunavukkarasu; Palanisamy, Nallasivam; Kalyana-Sundaram, Shanker et al. (2013) Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 110:3035-40|
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