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Gene-expression profile in a series of non-Hodgkin lymphoma (NHL) patients

ABSTRACT: PIM serine/threonine kinases are overexpressed, translocated or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types, and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBLC), follicular lymphoma (FL), marginal zone lymphoma-MALT type (MZL-MALT), chronic lymphocytic leukemia (CLL) and nodal marginal zone lymphoma (NMZL) cases. Increased PIM2 protein expression was associated with an aggressive clinical course in ABC-DLBCL patients. Pharmacological and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity, and indicated the involvement of PIM2 kinase in regulating mTORC1. The simultaneous genetic inhibition of all three PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32018 | GEO | 2011/10/17

SECONDARY ACCESSION(S): PRJNA147523

REPOSITORIES: GEO

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Project description:Lymphoplasmacytic lymphomas and marginal zone lymphomas of nodal, extra-nodal and splenic types account for 10% of non-Hodgkin lymphomas. They are similar at the cell differentiation level, sometimes making difficult to distinguish them from other indolent non-Hodgkin lymphomas. To better characterize their genetic basis, we performed array-based comparative genomic hybridization in 101 marginal zone lymphomas (46 MALT, 35 splenic and 20 nodal marginal zone lymphomas) and 13 lymphoplasmacytic lymphomas. Overall, 90.1% exhibited copy-number abnormalities. Lymphoplasmacytic lymphomas demonstrated the most complex karyotype (median=7 copy-number abnormalities), followed by MALT (4), nodal (3.5) and splenic marginal zone lymphomas (3). A comparative analysis exposed a group of copy-number abnormalities shared by several or all the entities with few disease-specific abnormalities. Gain of chromosomes 3, 12 and 18 and loss of 6q23-q24 (TNFAIP3) were identified in all entities. Losses of 13q14.3 (MIRN15A-MIRN16-1) and 17p13.3-p12 (TP53) were found in lymphoplasmacytic and splenic marginal zone lymphomas; loss of 11q21-q22 (ATM) in nodal, splenic marginal zone and lymphoplasmacytic lymphomas; loss of 7q32.1-q33 in MALT, splenic and lymphoplasmacytic lymphomas. Abnormalities affecting the NF-kB pathway were observed in 70% of MALT and lymphoplasmacytic lymphomas and 30% of splenic and nodal marginal zone lymphomas, suggesting distinct roles of this pathway in the pathogenesis/progression of these subtypes. Elucidation of the genetic alterations contributing to the pathogenesis of these lymphomas may guide to design specific therapeutic approaches. One hundred fourteen patients were included in this study: 46 MALT lymphomas (22 pulmonary, 11 salivary glands, 7 lacrimal glands and 6 gastrointestinal), 35 splenic marginal zone lymphomas, 20 nodal marginal zone lymphomas and 13 non-Waldenström’s Macroglobulinemia lymphoplasmacytic lymphomas. All cases were reviewed prior to study on paraffin sections with immunohistochemistry. Sections of each frozen tissue used for study were also reviewed by histological examination and immunohistochemistry before was submitted for the study.

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Gene-expression profile in a series of non-Hodgkin lymphoma (NHL) patients

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