Mantle cell lymphoma (MCL) bears the worst prognosis among B-cell non Hodgkin lymphomas, with a median survival of 3 years. Cases with leukemic MCL and splenomegaly without adenopathies may have a more indolent course when compared to patients with predominantly nodal disease. This difference is associated with a higher rate of mutated immunoglobulin heavy chain variable region (IGHV) genes and a less frequent expression of CD38. Aims. We investigated the gene expression profile of a cohort of leukemic nodal and non-nodal MCL to gain insights into the biologic features of these subgroups. Methods. Sixteen peripheral blood samples with >75% of clonal B-lymphocytes from untreated patients affected by MCL were evaluated by HGU133 Plus 2.0 arrays (Affymetrix). Diagnosis of MCL was supported in all cases by t(11;14)(q13;q32) and/or cyclin D1 detection. Statistical analysis, performed using the dChip software, was based on unsupervised and supervised approaches. Functional annotation and enrichment analyses were performed by DAVID and FATIGO softwares. IGHV sequencing followed ERIC recommendations. Results. Median age was 69 years; 10 patients (62%) were males; the median lymphocyte count was 12.3¥109/L (4.9-140.1). Twelve cases showed splenomegaly at presentation; 9 (56%) had palpable and/or deep lymphadenopathies (nodal group), while the remaining patients had no nodes (n=7, non-nodal group). IGHV mutational status, evaluable in 15 patients, proved unmutated in all nodal MCL (one third displayed IGHV3-21 gene) and mutated in all non-nodal MCL. CD38 was positive in 8/9 nodal and 1/5 non-nodal evaluable cases. T-test selected 389 differentially expressed genes and segregated samples in 2 clusters corresponding to nodal and non-nodal groups; non-nodal MCL appeared more homogeneous than nodal cases, that grouped into 2 subclusters; one included the three IGHV3-21 cases. In the nodal group, 291 genes were up-regulated and the gene categories over-represented were: apoptosis (p-value=8.5E-03), DNA repair/response to DNA damage (p-value=7.5E-02) and, to a lesser extent, cell proliferation (P=7.9E-02). Notably, a conspicuous number of up-regulated genes were related to TP53-pathway (MDM4, TP53INP1, ZNF148). In the non-nodal group, 98 genes were up-regulated with a prevalence of the lymphocyte activation terms (P=2.8E-04). Similarly, some genes that play a role in NFKB-pathway were up-regulated: MALT1, typically altered in MALT lymphoma; TNFRSF13B that regulates B-cell homeostasis; PRDX4 and FLNA that positively regulate NFKB-pathway. It is worth mentioning that BIC was over-expressed in this series. BIC processing can generate miR155, highly expressed in Hodgkin's lymphoma, diffuse large B-cell lymphomas and chronic lymphocytic leukemia. Interestingly, the comparison between the two gene lists by FATIGO highlighted a prevalence (P=9.36E-01) of genes involved in cell adhesion (IGAE, EZR, PCDH9) in the nodal group. Given the perfect overlap between clinical presentation and IGHV sequencing, these results reflect also the differences between mutated and unmutated MCL. Conclusions. These findings contribute to dissect the molecular mechanisms underlying the different clinical presentation of non-nodal MCL, characterized by mutated IGHV, up-regulation of lymphocyte activation genes and down-regulation of cell adhesion genes, and offer the rationale to explore their apparent different prognosis and improve the clinical management in a broadened cohort of patients.

NODAL AND NON-NODAL MANTLE CELL LYMPHOMAS DISPLAY A DIFFERENT GENOMIC PROFILE AND IGHV MUTATIONAL STATUS

CUNEO, Antonio;
2010

Abstract

Mantle cell lymphoma (MCL) bears the worst prognosis among B-cell non Hodgkin lymphomas, with a median survival of 3 years. Cases with leukemic MCL and splenomegaly without adenopathies may have a more indolent course when compared to patients with predominantly nodal disease. This difference is associated with a higher rate of mutated immunoglobulin heavy chain variable region (IGHV) genes and a less frequent expression of CD38. Aims. We investigated the gene expression profile of a cohort of leukemic nodal and non-nodal MCL to gain insights into the biologic features of these subgroups. Methods. Sixteen peripheral blood samples with >75% of clonal B-lymphocytes from untreated patients affected by MCL were evaluated by HGU133 Plus 2.0 arrays (Affymetrix). Diagnosis of MCL was supported in all cases by t(11;14)(q13;q32) and/or cyclin D1 detection. Statistical analysis, performed using the dChip software, was based on unsupervised and supervised approaches. Functional annotation and enrichment analyses were performed by DAVID and FATIGO softwares. IGHV sequencing followed ERIC recommendations. Results. Median age was 69 years; 10 patients (62%) were males; the median lymphocyte count was 12.3¥109/L (4.9-140.1). Twelve cases showed splenomegaly at presentation; 9 (56%) had palpable and/or deep lymphadenopathies (nodal group), while the remaining patients had no nodes (n=7, non-nodal group). IGHV mutational status, evaluable in 15 patients, proved unmutated in all nodal MCL (one third displayed IGHV3-21 gene) and mutated in all non-nodal MCL. CD38 was positive in 8/9 nodal and 1/5 non-nodal evaluable cases. T-test selected 389 differentially expressed genes and segregated samples in 2 clusters corresponding to nodal and non-nodal groups; non-nodal MCL appeared more homogeneous than nodal cases, that grouped into 2 subclusters; one included the three IGHV3-21 cases. In the nodal group, 291 genes were up-regulated and the gene categories over-represented were: apoptosis (p-value=8.5E-03), DNA repair/response to DNA damage (p-value=7.5E-02) and, to a lesser extent, cell proliferation (P=7.9E-02). Notably, a conspicuous number of up-regulated genes were related to TP53-pathway (MDM4, TP53INP1, ZNF148). In the non-nodal group, 98 genes were up-regulated with a prevalence of the lymphocyte activation terms (P=2.8E-04). Similarly, some genes that play a role in NFKB-pathway were up-regulated: MALT1, typically altered in MALT lymphoma; TNFRSF13B that regulates B-cell homeostasis; PRDX4 and FLNA that positively regulate NFKB-pathway. It is worth mentioning that BIC was over-expressed in this series. BIC processing can generate miR155, highly expressed in Hodgkin's lymphoma, diffuse large B-cell lymphomas and chronic lymphocytic leukemia. Interestingly, the comparison between the two gene lists by FATIGO highlighted a prevalence (P=9.36E-01) of genes involved in cell adhesion (IGAE, EZR, PCDH9) in the nodal group. Given the perfect overlap between clinical presentation and IGHV sequencing, these results reflect also the differences between mutated and unmutated MCL. Conclusions. These findings contribute to dissect the molecular mechanisms underlying the different clinical presentation of non-nodal MCL, characterized by mutated IGHV, up-regulation of lymphocyte activation genes and down-regulation of cell adhesion genes, and offer the rationale to explore their apparent different prognosis and improve the clinical management in a broadened cohort of patients.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1401592
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