McPhail, Ellen Darcy

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1 + Lin − hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.

Abstract Purpose: Only a limited number of genetic studies have been conducted in primary central nervous system lymphomas (PCNSL), partly due to the rarity of the tumors and the very limited amount of available tissue. In this report, we present the first molecular characterization of copy number abnormalities (CNA) of newly diagnosed PCNSL by array-based comparative genomic hybridization (aCGH) in formalin-fixed paraffin-embedded (FFPE) specimens and compare the results with matched, frozen tumor specimens. Experimental Design: We conducted aCGH in FFPE tissues from PCNSL. Results were compared with matched, paired, frozen tumors. Results: Our analysis confirmed the good to fair quality and reliability of the data generated from limited amounts of tumoral FFPE tissue. Overall, all PCNSL cases were characterized by highly complex karyotypes, with a median of 23 CNAs per patient (range, 17–47). Overall, 20 chromosomal regions were recurrently found in more than 40% of cases. Deletions of 6p21, 6q, and 9p21.3 and gain of 12q12-q24.33 were the commonest CNAs. Other minimal affected regions were defined, and novel recurrent CNAs affecting single genes were identified in 3q26.32 (TBL1XR1) and 8q12.1 (TOX). Conclusions: The results obtained are encouraging. Larger archival tissue collections can now be analyzed to complement the still fragmented knowledge we have of the genetic basis of the PCNSL. Clin Cancer Res; 17(13); 4245–53. ©2011 AACR.

Abstract Diffuse large B-cell lymphoma (DLBCL) can be separated for prognostic purposes using gene expression profiling (GEP) into 2 subgroups: germinal center B-cell (GCB) and activated B-cell phenotypes. However, GEP is impractical for routine clinical use, and immunophenotyping is an imperfect surrogate. Therefore, we studied the relationship between expression of the purported germinal center marker LMO2 and the presence of IGH-BCL2 fusions, BCL6 translocations, and LMO2 translocations. In addition, we investigated the usefulness of LMO2 expression as a marker of GCB subtype in DLBCL. Immunohistochemical and fluorescence in situ hybridization studies were successfully performed on 101 cases of de novo DLBCL that had been incorporated into a tissue microarray. There was a statistically significant association between IGH-BCL2 fusion and LMO2 protein expression (P = .02) but not between BCL6 translocations and LMO2 expression. LMO2 translocations were not identified. Although uncommon, all cases that had both IGH-BCL2 fusion and BCL6 translocations expressed LMO2. The findings suggest LMO2 as a potential marker for the GCB phenotype.

Abstract A diagnosis of composite lymphoma is typically prompted by the observation of morphologic discordance. We present a case of a spleen revealing histologic features of follicular lymphoma, without any indication of a second lymphoma. Immunohistochemical stains supported this diagnosis and showed the follicular lymphoma to be BCL2–. However, these studies revealed 2 additional unexpected findings: cyclin D1+ mantle zone cells surrounding neoplastic and reactive follicles (indicative of in situ mantle cell lymphoma) and BCL2-bright, histologically nonneoplastic follicles (indicative of in situ follicular lymphoma). ImmunoFISH and microdissection and polymerase chain reaction analysis documented the clonal nature of the cyclin D1+ mantle zones and illustrated clonal independence from the follicular lymphoma. This case illustrates an uncommon and unusual composite follicular and mantle cell lymphoma, with the follicular lymphoma accompanied by an in situ component, whereas the only manifestation of the mantle cell lymphoma was in situ.

Abstract We conducted comprehensive gene expression profiling (GEP) of primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma (n = 33) and compared the results to GEP of other B- and T-cell lymphomas and normal lymphocytes to identify novel markers and deregulated pathways. MALT has a prominent T-cell signature and a marginal zone/memory B-cell profile. Four novel transcripts were specifically overexpressed in MALT, and 2 of these, MMP7 and SIGLEC6, were validated at the protein level. GEP also revealed distinct molecular subsets in MALT. One subset, characterized by MALT1 translocations, showed overexpression of nuclear factor-κB (NF-KB) pathway genes but also was enriched for chemokine signaling pathways. Another subset showed increased plasma cells and a prominent plasma cell gene signature. By analyzing several genes with very high (“spiked”) expression in individual cases, we identified clusters with different biologic characteristics, such as samples with MALT1 translocations having high expression of MALT1 and RARA, samples with plasmacytic differentiation having high FKBP11 expression, and samples with high RGS13 expression tending to have trisomy 3 and reactive follicles. In conclusion, MALT subgroups with distinct pathologic features defined by distinct groups of deregulated genes were identified. These genes could represent novel diagnostic and therapeutic targets.

Purpose Primary CNS lymphoma (PCNSL) is an aggressive lymphoma but clinically validated biologic markers that can predict natural history to tailor treatment according to risk are lacking. Several genetic changes including BCL6 rearrangements and deletion of 6q22, containing the putative tumor suppressor gene PTPRK, are potential risk predictors. Herein we determined the prevalence and survival impact of del(6)(q22) and BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements in a large PCNSL cohort treated in a single center. Patients and Methods Interphase fluorescence in situ hybridization was performed using two-color probes for BCL6, MYC, IGH-BCL6, and del(6)(q22) on thin sections of 75 paraffin-embedded samples from 75 HIV-negative, immunocompetent patients newly diagnosed with PCNSL. Survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and proportional hazards regression adjusting for age, deep structure involvement, and high-dose methotrexate (HDMTX) treatment. Results The prevalence of del(6)(q22) and BCL6, IGH, and MYC translocations was 45%,17%, 13%, and 3%, respectively. The presence of del(6)(q22) and/or a BCL6 translocation was associated with inferior overall survival (OS; P = .0097). The presence of either del(6)(q22) alone or a BCL6 translocation alone was also associated with inferior OS (P = .0087). Univariable results held after adjusting for age, deep structure involvement, and HDMTX. Conclusion Del (6)(q22) and BCL6 rearrangements are common in PCNSL and predict for decreased OS independent of deep structure involvement and HDMTX. Unlike systemic diffuse large B-cell lymphoma, del(6)(q22) is common and IGH translocations are infrequent and usually involve BCL6 rather than BCL2, suggesting a distinct pathogenesis.

AbstractCentrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene expression–based centrosome index (CI) that correlated with centrosome amplification and was an independent prognostic factor in a small cohort of heterogeneously treated patients. In this study, we validated the prognostic significance of the CI in 2 large cohorts of patients entered into clinical trials and showed that a high CI is a powerful independent prognostic factor in both newly diagnosed and relapsed patients, whether treated by intensive therapy (total therapy II) or novel agents (bortezomib). Tumors with high CI overexpressed genes coding for proteins involved in cell cycle, proliferation, DNA damage, and G2-M checkpoints, and associated with the centrosome and kinetochore/ microtubules. In particular, aurora kinases are significantly overexpressed in patients with high CI, with concordant increase in protein expression. Human myeloma cell lines with higher CI are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis.

AbstractLittle effort has been made to quantitate adverse outcomes of monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin M (IgM) class, which progresses to lymphoma or Waldenström macroglobulinemia, whereas IgA and IgG MGUS progress to multiple myeloma, primary amyloidosis (AL), or a related plasma cell disorder. From 1960 to 1994, IgM MGUS was diagnosed in 213 patients in southeastern Minnesota. The end point was progression to lymphoma or a related disorder, as assessed with the Kaplan-Meier method. The 213 patients were followed up for 1567 person-years (median, 6.3 years per patient). Lymphoma developed in 17 patients (relative risk [RR], 14.8), Waldenström macroglobulinemia in 6 (RR, 262), primary amyloidosis in 3 (RR, 16.3), and chronic lymphocytic leukemia in 3 (RR, 5.7). The relative risk of progression was 16-fold higher in the patients with IgM MGUS than in the white population of the Iowa Surveillance, Epidemiology, and End Results Program. Cumulative incidence of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years. On multivariate analysis, the serum monoclonal protein and serum albumin concentrations at diagnosis were the only risk factors for progression to lymphoma or a related disorder. Risk for progression to lymphoma or a related disorder at 10 years after the diagnosis of MGUS was 14% with an initial monoclonal protein concentration of 0.5 g/dL or less, 26% with 1.5 g/dL, 34% for 2.0 g/dL, and 41% for more than 2.5 g/dL. (Blood. 2003;102:3759-3764)