The prognostic role of the transcription factor SOX11 in mantle cell lymphoma (MCL) is controversial. We investigated prognostic markers in a population-based cohort of 186 MCL cases. Seventeen ...patients (9%) did not require any therapy within the first 2 years after diagnosis and were retrospectively defined as having an indolent disease. As expected, indolent MCL had less frequent B symptoms and extensive nodal involvement and 88% of these cases expressed SOX11. In our cohort 13 cases (7.5%) lacked nuclear SOX11 at diagnosis. SOX11− MCL had a higher frequency of lymphocytosis, elevated level of lactate dehydrogenase (LDH), and p53 positivity. The overall survival in the whole cohort, excluding 37 patients receiving autologous stem cell transplantation, was 3.1 year and in patients with indolent or nonindolent disease, 5.9 and 2.8 years, respectively (P = .004). SOX11− cases had a shorter overall survival, compared with SOX11+ cases, 1.5 and 3.2 years, respectively (P = .014). In multivariate analysis of overall survival, age > 65 (P = .001), Eastern Cooperative Oncology Group score ≥ 2 (P = .022), elevated LDH level (P = .001), and p53 expression (P = .001) remained significant, and SOX11 lost significance. We conclude that most indolent MCLs are SOX11+ and that SOX11 cannot be used for predicting an indolent disease course.
The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from ...13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.
The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor ...samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy.
The microenvironment influences outcome in follicular lymphoma. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should ...be demonstrable in the same analysis and in competition with clinical factors.
Seventy follicular lymphoma patients with extreme clinical outcome ("poor" and "good" cases) were selected in a population-based cohort of 197. None of the 37 good-outcome patients died from lymphoma, whereas all the 33 poor-outcome patients succumbed in <or=5 years. Furthermore, the good-outcome patients were followed for a long time and needed no or little treatment. A tissue microarray was constructed from diagnostic, pretreatment biopsies. Cellular subsets were quantified after immunostaining, using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). Flow cytometry data from the same samples were also used.
Independently of the Follicular Lymphoma International Prognostic Index, CD4(+) cells were associated with poor outcome and programmed death-1-positive and CD8(+) cells were associated with good outcome. The prognostic values of CD4(+) and programmed death-1-positive cells were accentuated when they were follicular and that of CD8(+) cells were accentuated when they were interfollicular. Follicular FOXP3(+) cells were associated with good outcome and interfollicular CD68(+) cells were associated with poor outcome. Additionally, high CD4/CD8 and CD4 follicular/interfollicular ratios correlated with poor outcome.
There are many important immune cell subsets in the microenvironment of follicular lymphoma. Each of these is independently associated with outcome. This is the first study showing the effect of the balance of the entire microenvironment, not only of individual subsets.
The results of immunohistochemical class prediction and prognostic stratification of diffuse large B-cell lymphoma (DLBCL) have been remarkably various thus far. Apart from biologic variations, this ...may be caused by differences in laboratory techniques, scoring definitions, and inter- and intraobserver variations. In this study, an international collaboration of clinical lymphoma research groups from Europe, United States, and Canada concentrated on validation and standardization of immunohistochemistry of the currently potentially interesting prognostic markers in DLBCL.
Sections of a tissue microarray from 36 patients with DLBCL were stained in eight laboratories with antibodies to CD20, CD5, bcl-2, bcl-6, CD10, HLA-DR, MUM1, and MIB-1 according to local methods. The study was performed in two rounds firstly focused on the evaluation of laboratory staining variation and secondly on the scoring variation.
Different laboratory staining techniques resulted in unexpectedly highly variable results and very poor reproducibility in scoring for almost all markers. No single laboratory stood out as uniformly poor or excellent. With elimination of variation due to staining, high agreement was found for CD20, HLA-DR, and CD10. Poor agreement was found for bcl-6 and Ki-67. Optimization of techniques and uniformly agreed on scoring criteria improved reproducibility.
This study shows that semiquantitative immunohistochemistry for subclassification of DLBCL is feasible and reproducible, but exhibits varying rates of concordance for different markers. These findings may explain the wide variation of biomarker prognostic impact reported in the literature. Harmonization of techniques and centralized consensus review appears mandatory when using immunohistochemical biomarkers for treatment stratification.
A subset of hematologic cancer patients is refractory to treatment or suffers relapse, due in part to minimal residual disease, whereby some cancer cells survive treatment. Cell-adhesion-mediated ...drug resistance is an important mechanism, whereby cancer cells receive survival signals
interaction with e.g. stromal cells. No genome-wide studies of
systems have yet been performed to compare gene expression in different cell subsets within a co-culture and cells grown separately. Using RNA sequencing and species-specific read mapping, we compared transcript levels in human Jeko-1 mantle cell lymphoma cells stably adhered to mouse MS-5 stromal cells or in suspension within a co-culture or cultured separately as well as in stromal cells in co-culture or in separate culture. From 1050 differentially expressed transcripts in adherent mantle cell lymphoma cells, we identified 24 functional categories that together represent four main functional themes, anti-apoptosis, B-cell signaling, cell adhesion/migration and early mitosis. A comparison with previous mantle cell lymphoma and chronic lymphocytic leukemia studies, of gene expression differences between lymph node and blood, identified 116 genes that are differentially expressed in all three studies. From these genes, we suggest a core set of genes (
) characteristic of cells undergoing cell-adhesion-mediated microenvironment signaling in mantle cell lymphoma/chronic lymphocytic leukemia. The model system developed and characterized here together with the core gene set will be useful for future studies of pathways that mediate increased cancer cell survival and drug resistance mechanisms.
Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic ...effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in >60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenalidomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with del(5)(q31). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover, lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with the VSIG4, PPIC, TPBG, activin A, and SPARC genes up-regulated by >2-fold in all samples and many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, down-regulated in most samples. Activin A, one of the most significant differentially expressed genes between lenalidomide-treated cells from MDS patients and healthy controls, has pleiotropic functions, including apoptosis of hematopoietic cells. Up-regulation and increased protein expression of the tumor suppressor gene SPARC is of particular interest because it is antiproliferative, antiadhesive, and antiangiogenic and is located at 5q31-q32, within the commonly deleted region in MDS 5q- syndrome. We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with del(5)(q31). SPARC may play a role in the pathogenesis of the 5q- syndrome.
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