| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
1 Molecular Pathology Program and
2 Biotechnology Program, Centro Nacional de Investigaciones Oncológicas, Madrid;
3 Department of Genetics and Pathology, Hospital Virgen de la Salud, Toledo;
4 Department of Pathology, Hospital Ramón y Cajal, Madrid;
5 Department of Hematology and Medical Oncology, Hospital Clínico, University of Valencia, Valencia;
6 Department of Pathology, Hospital General Universitario Gregorio Marañón, Madrid; and
7 Department of Hematology, Hospital Nuestra Señora del Prado, Talavera de la Reina, Toledo, Spain
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
MCL signature (446 genes) includes genes involved in apoptosis, cell cycle, signal transduction, and cell structure. Especially striking was the presence of multiple concurrent alterations in the tumor necrosis factor and nuclear factor 
B pathway, and the overexpression of IL10R and SPARC genes. We also identified a molecular signature for the presence of immunoglobulin variable heavy chain somatic mutation, which includes a number of genes potentially relevant in cancer (CDC14A, ras, and others). Signatures for proliferation and blastoid cytology were also found.
An integrated analysis of these data yields a gene-expression based survival predictor (26 genes grouped into two clusters), which distinguishes half of the patients with a survival probability of 52% at 5 years. The predictive model has been confirmed by cross-validation.
In conclusion, MCL seems to combine a disease-specific signature and different sets of genes of which the expression is associated with key clinical, molecular, and immunophenotypical events.
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Despite the presence of this common molecular marker, experiments with transgenic mice overexpressing CCND1 show that this protein alone cannot induce lymphomas and requires other oncogenic factors, such as c-myc or others (4) . Thus, different mechanisms must be required for the development and progression of MCL (5) . The loss of the chromosomal fragment 11q22–23, where the ataxia-telangiectasia mutated gene (ATM) is located, has been identified recently (6) . This deletion affects almost 50% of MCLs, and it has been proposed that loss of ATM function may occur early in the malignant transformation of follicle mantle cells. Nevertheless, there must be currently unknown mechanisms that act in conjunction with these already characterized alterations in MCL. For instance, the knowledge of the molecular changes acquired in MCL cells is insufficient to explain fully the resistance to apoptosis that characterizes this tumor, in which treatment resistance to the commonly used drugs seems to be a cardinal feature.
Different clinical and molecular observations taken together highlight the molecular heterogeneity of MCL. Although it was initially claimed that MCL cells were derived from naive pre-GC B cells, recent studies have shown that around 25–30% of MCLs carry mutations in the IgVH (7 , 8) . This is a characteristic feature of post-Germinal Centre cells and may indicate that a subset of MCLs originates from B cells exposed to the Germinal Centre environment. Whether the presence of IgVH somatic mutations is merely an epiphenomenon or is related to some underlying molecular variability is still unresolved.
A more comprehensive knowledge of the underlying molecular alterations in MCL should also permit their correlation with clinical course in these patients, and, specifically, the identification of subsets of patients with relatively indolent or highly aggressive courses.
Here we have chosen to explore the constellation of molecular abnormalities in MCL through expression profiling, and to correlate these profiles with a number of molecular (IgVH somatic mutation), immunohistological (increased proliferation fraction), and clinicopathological features of the tumors. This study supplements the data published previously of expression profiling in series of MCL, and joins a large enough series of cases with detailed molecular and immunophenotypical studies that allow for the proposal of molecular signatures for survival, blastoid variant, and IgVH somatic mutation.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
For the expression profile analysis, only frozen tissues from lymph node biopsies collected at the moment of diagnosis were used. Mantle B cells isolated from reactive tonsillectomy specimens were used as controls.
Patient medical records were reviewed to gather information on age, gender, localization, and stage of disease at diagnosis, International Prognostic Index, and disease course. All of the patients received chemotherapy for curative purposes.
Isolation of Mantle B Cells.
Tonsil specimens were obtained from patients undergoing routine tonsillectomy for chronic tonsillitis. Tonsillar cell suspensions were obtained by mincing the tissue in ice-cold culture medium (RPMI 1640) and leaving it to sediment for 5 min. Mononuclear cells were isolated by Ficoll-Paque Plus (Amersham Pharmacia Biotech AB, Uppsala, Sweden).
B-cell isolation from mononuclear cell fraction was performed by immunomagnetic bead selection with a CD19 multisort kit (Miltenyi Biotech, Auburn, CA) following the manufacturer’s instructions. B-cell purity of >90% homogeneity was confirmed by three-color flow cytometry using CD19/CD27/CD45.
CD27-negative/CD19-positive/CD45-positive cells were selected as the negative fraction, after incubation with CD27 microbeads (Miltenyi Biotech) conjugated with monoclonal mouse antihuman CD27 antibodies. CD19-positive, CD27-negative cells were incubated with rabbit antihuman IgD FITC-FITC (DAKO) and with anti-FITC microbeads, and the positive cells were collected.
The purity of the tonsillar mantle cells (CD19+, CD27-, and IgD+) obtained by this method was 84%, as confirmed by flow cytometry (FAC Sort; Becton Dickinson, San Jose, CA) using the Paint a Gate program (Becton Dickinson).
RNA Extraction and Amplification.
Total RNA was isolated in two steps using TRIzol (Life Technologies, Inc., Grand Island, NY) followed by RNeasy (Qiagen Inc., Valencia, CA) purification. The integrity of RNA was verified by electrophoresis. Double-strand cDNA was synthesized from 4 µg of total RNA using the Superscript System for cDNA synthesis (Life Technologies, Inc.). In vitro transcription was carried out using the T7 Megascript in vitro transcription kit (Ambion, Austin, TX). The quality of the amplified RNA produced was checked by electrophoresis and its concentration measured.
Microarray Procedures.
Five µg of amplified RNA from each sample was directly labeled with cyanine 3-conjugated dUTP (Cy3), whereas 5 µg of aRNA from the Universal Human Reference RNA (Stratagene) was labeled with cyanine 5-conjugated dUTP (Cy5) as reference. For all of the microarray studies the CNIO OncoChip was used (12)
. Hybridizations were performed as described (12)
. After washing, the slides were scanned using a Scanarray 5000 XL (GSI Lumonics Kanata, Ontario, Canada) and images were analyzed with the GenePix 4.0 program (Axon Instruments Inc., Union City, CA).
Data Analysis and Clustering.
Data obtained from each hybridization were stored in a database for analysis. The Cy3:Cy5 ratios were normalized to the median ratio value of all of the spots in the array. After normalization, spots with intensities for both channels (sum of medians) less than that of the local background were discarded. The ratios of the remaining spots were log-transformed (base 2), and duplicated spots on the OncoChip were averaged to the median. In addition, any gene of which the data were missing from >30% of the samples was not included in subsequent analyses. For supervised prediction, missing values for the remaining spots were replaced by the average value of the nearest K patterns (K = 17; Ref. 13
). To obtain the expression profile of each tumor we referred the ratios of the tumors to the control. The cluster analysis was done with the Gene Cluster program (14)
.
Supervised Prediction.
Classes were defined with respect to several variables: somatic mutation status, proliferation level, and OS. For somatic mutation and proliferation signatures marker genes were identified using Student’s t test. These procedures are available for inspection.9
IgVH Study.
IgVH mutational analysis was performed on 35 of the 38 MCL samples. A detailed description of the IgVH findings in these cases has been published separately (8)
. Rearranged IgVH genes were amplified using a seminested PCR method, as described previously (15)
. A sequence was considered mutated when there was <98% homology with the closest germ-line VH genes.
Immunohistochemistry.
An immunohistochemical analysis was carried out to evaluate some of the cDNA-microarray results at the protein level. It was carried out on a Tissue-Microarray containing samples of 32 MCL cases included in this series. The BclII, Bcl6, cyclin D1 (DAKO, Copenhagen, Denmark), and p18 (Santa Cruz Biotechnology, Santa Cruz, CA) antibodies were used for this purpose.
The proliferation index used to construct the "increased proliferation fraction signature" was quantitatively evaluated using MIB1 antibody (DAKO). At least 200 cells were counted in every case. The cutoff was 50% of positive cells; thus, a low proliferation index was 
50% of positive cells and a high proliferation index was >50%.
Statistics.
OS curves were derived using the Kaplan-Meier method. All of the deaths were attributed to the tumor. Statistical significance of associations between individual variables and OS was determined using the log-rank test. Cox’s univariate proportional hazard analysis was also performed independently for each variable. Multiple testing and the random permutation test validated results. To build the gene expression-based predictive model, genes with values of P < 0.05 in the Cox’s univariate analysis were grouped by their expression profile using the SOTA program.10
Nine groups of predictor genes were obtained. The average of the expression ratio, in each cluster, was used to perform a conditional backward Cox’s multivariate analysis.
The result of the Cox’s multivariate analysis was then validated using a prediction model derived by discriminant analysis. In this model, patients were stratified by the median survival in the series: short- versus long-term survival (< versus >27 months, respectively). For patients who remained alive, only those with >27 months of follow-up were included. General applicability of the model was also tested by leave-one-out cross-validation.
Statistical analyses were performed using the SPSS (SPSS Inc., Chicago, IL) program and the tools for random permutation tests available.10
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
MCL Displays a Relatively Homogeneous Profile.
Thirty-eight MCL samples and one MCL cell line (Granta 519) were analyzed by cDNA microarray technology. Unsupervised clustering revealed a relatively homogeneous expression profile, grouping all of the clinical samples in one main cluster (Fig. 1)
. The MCL cell line Granta 519 was grouped separately, probably because of all of the intrinsic molecular alterations that this cell line carries. To confirm the reproducibility of the technique, we repeated the hybridization of four of the samples and analyzed them together. Different hybridizations corresponding to the same patient clustered together using unsupervised clustering, demonstrating that the expression profiles obtained were reproducible.
|
. As expected, CCND1 was up-regulated in the whole series, and so contributed to validate the data of the expression profiling. A large set of genes involved in important cellular processes, like apoptosis, cell cycle control, or signaling, was found to be consistently deregulated in the majority of MCL samples.
|
. The most remarkable were the antiapoptotic genes BCL2 and TOSO, of which the expression levels were 5.8- and 4.6-fold higher in lymphomas than in the control. An important number of genes related with TNF and NFB pathways were found up-regulated in our series of MCL, including the activator of NFkB, IKBKB, TNFRSF7, TNFS4, TANK, TRAF5, TRAF6, and DED. On the other hand, the proapoptotic genes CSE1L, CASP7, STK17A, and STK17B were lost in our tumor series.
|
. All of the alterations found in this group of genes were losses, thus being consistent with the relatively low rate of proliferation that characterizes this tumor. Thus, the CDK inhibitor p18 was expressed at a very low level in our series. Some cyclins, CCNH, CCNG2, PCNA, CCNA2, CCNB1, and CCNB2, and several cell cycle-division proteins, cdc25a, cdc25c, cdc6, cdc45-l, and CHEK-1, were also lost (see supplementary data11
).
The largest functional group deregulated in this series is the signal transduction-related group of proteins, with 25 and 33 genes >2-fold down- and up-regulated, respectively. Other remarkably deregulated genes involving different cell functions are described in Table 3
, and in the supplementary data.11
The most relevant were SPARC and IL10R, because of their very high level of expression in the series of MCL (11.5- and 9.1-fold, respectively).
|
, thus validating the cDNA microarray results. Only 1 case presented positive expression of p18 in the paraffin-embedded tissue, the MCL case having a stronger signal in the cDNA microarray.
|
IgVH Somatic Mutation Signature.
To derive the molecular signature for somatic mutation, we did a Student’s t test and selected the 15 genes with the lowest P (Fig. 3A)
. MCL cases with >2% somatic mutations showed up-regulation (compared with those cases without somatic mutation) of some genes involved in DNA and RNA processing, such as the gene encoding for the DNA replication-related protein RPA1, the helicase SMARCA5, and the splicing factor SFRS3. K-ras2 was up-regulated, as was FNTA, a post-transcriptional modifier of Ras and other G proteins. The levels of the transcription factor EGR2 were also higher in MCL cases with mutation. Finally, CDC14A, a regulator of p53 function, was found to be overexpressed in this group.
|
. Blastoid cases had a lower expression of caspase 7, but an increased expression of TOP1 and CDK4 (with a lower significance).
Increased Proliferation Fraction Signature.
The proliferation rate of the tumors was examined using Ki-67 expression, as detected by immunohistochemistry (MIB1 antibody). Fourteen cases presented high expression of Ki-67 (>50% positive cells), and the other 24 had low levels of Ki-67. The most relevant finding was the down-regulation of BIK, a BCL2-interacting proapoptotic protein, observed in the group of cases with higher proliferation.
Survival Analysis.
A number of 137 genes were found to predict OS probability using Cox’s univariate analysis. These genes were clustered into nine groups according to their expression profile. The average ratio of expression for each group was then calculated, and a backward Cox’s multivariate analysis identified two clusters (containing 26 genes), which independently predict survival (see supplementary data11
). The patients were ranked according to their score and divided into two groups of similar size (16 and 15 patients). Their survival probability was then estimated by the Kaplan-Meier method. The first group, with the lowest score, displayed a survival probability of 52% at 5 years (Fig. 4)
.
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The comparison with the expression profile of normal mantle zone B cells allows it to be recognized that, in addition to the increased cyclin D1 expression, there is a marked deregulation of 446 genes, present in at least 50% of the cases. This signature includes genes described as playing critical roles in apoptosis, cell cycle, signal transduction, cell structure, cytoskeleton, and so forth. The overexpression of cyclin D1 in this series was observed in all of the series of cases, thus being independent of the normalization with mantle zone cells.
Especially informative is the deregulation of a significant number of genes involved in apoptosis control. Thus, there is a simultaneous loss of a large set of proapoptotic genes including CASP7, STK17A, STK17B, and CSE1L. Caspase 7 is a well-characterized executioner caspase (16)
, whereas STK17A and STK17B, also named as DRAK1 and DRAK2, are kinases involved in the initiation of apoptosis (17)
. CSE1L is a nuclear transport factor that was first cloned while searching for genes that rendered breast cancer cells resistant toward toxin-induced apoptosis (18)
. On the other hand, some antiapoptotic genes, such as BCL2 and TOSO (see Table 2
), are up-regulated in our series. BCL2 is known to block apoptosis, regulating the permeability of the outer mitochondrial membrane (19)
, whereas TOSO inhibits Fas-mediated apoptosis in lymphoid cells, resulting in the inhibition of caspase activity (20)
. Another antiapoptotic gene considerably up-regulated is phosphatidylinositol 3'-kinase catalytic, 
polypeptide (p13K), a class I P13K (21)
, related with drug resistance mechanisms in leukemic cells (22)
.
In the same context, the simultaneous deregulation of multiple genes implicated in the regulation of the NFB, and more specifically in the routes that interlink TNF with NFB, is very remarkable. Thus, it appears to be an important up-regulation of the main genes of this pathway, such as TNFRSF7, TNFS4, TANK, TRAF5, TRAF6, DED, and others. This is also detectable for IkBkB, of which the product activates NFB. It has been demonstrated recently that IkBkB, besides the central role that it plays in the antiapoptotic pathway controlled by NFB, can also suppress p53 protein stabilization through up-regulation of Mdm2 (23)
.
Taking these findings together, the amount and relevance of apoptosis-regulator genes found to be altered in MCL, including the mitochondrial apoptotic pathway (up-regulation of BCL2) and the TNF and NFB pathways, probably accounts for the low sensitivity of MCL tumor cells to chemotherapy, and the subsequent poor outcome of MCL patients. This is consistent with previous observations (24)
that have already emphasized the noticeable accumulation of alterations in apoptosis-regulator genes.
In addition to these significant findings in relation to apoptosis, strong up-regulation of IL10R and SPARC found in MCL constitutes a potentially important observation. IL-10 is an autocrine growth factor, important for B-cell survival, and needed for the expansion of malignant B cells (25 , 26) . It has been demonstrated to be up-regulated in human peripheral B cells as a consequence of CD5 expression. Thus, CD5 supports the survival of B cells by stimulating IL-10 production, and by concurrently exerting negative feedback on B-cell receptor (BCR)-induced signaling events that can promote cell death (27) . Up-regulation of IL-10R in MCL has been detected recently by expression profiling in a smaller series of seven cases, but at a lower level (1.9-fold versus 9.1-fold in our study; Ref. 10 ). The increased expression of IL-10 could be also related with the diminished presence of inflammatory T cells in MCL samples, because IL-10 has been demonstrated to be a potent immunosuppresser (28) . Moreover, it has been shown that diffuse large B-cell lymphomas expressing CD5 are more aggressive than their CD5-negative- counterparts (29) . Consistently with these observations, the data obtained here also show an increased expression of CD5 mRNA, as might be expected, because a majority of MCL cases regularly express CD5.
SPARC has been also found to be strongly up-regulated in this series (11.5-fold, on average). The product of SPARC, also known as osteonectin and BM-40, is a secreted, multifunctional, extracellular matrix glycoprotein, which inhibits cell adhesion and activates MMP2. SPARC is involved in diverse biological processes related with angiogenesis, and tumor cell migration and invasion (30) , and has been observed to be overexpressed in multiple myeloma (31) .
In addition to increased cyclin D1 expression, alterations in cell-cycle machinery mainly involve loss of relevant genes in control of cell cycle progression. A notable finding is the loss of p18, observed in most cases, which confirms a previous report of alterations of this CDKI in 2 MCL cases (32) . More recently, other authors (33) , based on p18 induction assays in multiple myeloma cell lines, showed the importance of this protein in the induction of tumor regression dependent of apoptotic cell death.
This study has also revealed the presence of a characteristic signature associated with IgVH somatic mutation, independent of those identified for blastoid cytology, survival, or proliferation. Recent studies have demonstrated that a significant fraction of MCL cases carry >2% of IgVH mutations (7 , 8) , although this finding lacks any prognostic significance. Cases included in this series bearing these IgVH somatic mutations display changes in the level of expression of a set of genes that includes CDC14A, a phosphatase of which the deregulated expression abolishes the centrosome division cycle and leads to chromosome missegregation, thus implying a role in multistep tumorigenesis and promotion of chromosomal instability (34) . The biological relevance of IgVH somatic mutation is given additional weight by the observed association with increased K-ras and farnesyl transferase expression, both of which are indicative of ras activation. Nevertheless, the exact role of somatic mutation in MCL needs additional investigation in a larger set of cases, to clarify whether it is merely an epiphenomenon, or whether indeed the presence of somatic mutation is pathogenically associated with critical genetic changes.
This analysis has also identified a molecular signature associated with blastoid cytology. Thus, the 5 cases analyzed differentially express a large set of molecules, including some associated with proliferation (gain of TOP1), apoptosis (loss of caspase 7), and vesicular transport (loss of RAB27A). Significantly, a striking increase of CDK4, an oncoprotein of which the amplification has been described in blastoid MCL (35) , has been observed here, thus confirming previous observations (36) .
We also attempted to obtain a molecular signature characteristic for a group of MCL with a high proliferation rate. As expected, we found a higher level of expression of several cyclins and other proliferation markers in the high proliferation rate group. One unexpected finding was the presence of a striking loss of the expression of BIK in the high proliferation rate group. This is an apoptosis promoter, downstream target, and effector in the E1A-induced p53 cell death pathway, and canonical member of the BH3-only family, which interacts with the cellular survival-promoting proteins, Bcl-2 and Bcl-xL (37) .
Despite the fatal prognosis of MCL, different observations coincide to highlight the presence of a group of patients with a more favorable course and better response to chemotherapy. The vast amount of data collected here allows a survival predictor to be derived that identifies a subset of patients with a 52% probability of 5-year survival. If confirmed in a blind set of cases, these data would allow MCL patients to be stratified according to their individual risk and would eventually enable the use of risk-tailored treatment protocols. The information accumulated should also facilitate the search for therapeutic targets, which could eventually contribute to a more rational treatment and improved prognosis in this lymphoma subtype. The predictor here proposed differs from that described recently, based on a gene expression signature related with proliferation (9) . Here, although a group of genes related with proliferation were present in the set of predictor genes (8 of 137 genes), the restriction to this proliferation cluster in the survival analysis reduces the capacity of the predictor (data not shown). Additionally, in our series cyclin D1 expression did not appear as a significant prognosis predictor.
In summary, this work demonstrates the existence of a constellation of gene-expression differences in MCL compared with normal mantle B cells. As well as the already known alterations, such as the increase in cyclin D1 expression, these data confirm that MCL cells are subject to a profound deregulation of multiple genes and pathways, singularly those in charge of regulation of apoptosis. Additionally, these data allow us to recognize some underlying molecular events associated with the presence of blastoid cytology, IgVH somatic mutation, and to identify a subset of genes of which the expression is associated with longer-term survival. Experimental and clinical validation in a larger series of cases could allow confirmation of these data, facilitating a more rational approach to the diagnosis and risk-tailored treatment of MCL cases.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Miguel Angel Piris, Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain. Phone: 34-91-224-69-00; Fax: 34-91-224-69-23; E-mail: mapiris{at}cnio.es
8 The abbreviations used are: MCL, mantle cell lymphoma; IgVH, immunoglobulin variable heavy chain; OS, overall survival; TNF, tumor necrosis factor; NFB, nuclear factor B; IL, interleukin. 
9 Internet address: http://bioinfo.cnio.es/cgi-bin/tools/multest/multest.cgi.
10 Internet address: http://bioinformatica.cnio.es/.
11 Internet address: http://redlinfomas.cnio.es/publications/molecular_signature.
Received 3/ 6/03. Revised 5/20/03. Accepted 9/19/03.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
in cutaneous T-cell lymphoma. Am. J. Pathol., 161: 1825-1837, 2002.This article has been cited by other articles:
|
|
 |
|
  P. Gelebart, M. Anand, H. Armanious, A. C. Peters, J. Dien Bard, H. M. Amin, and R. Lai Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma Blood, December 15, 2008; 112(13): 5171 - 5179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wu, H. P. Cho, D. B. Rhee, D. K. Johnson, J. Dunlap, Y. Liu, and Y. Wang Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication J. Cell Biol., October 14, 2008; 181(3): 475 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Tracey, M. Aggarwal, M. Garcia-Cosio, R. Villuendas, P. Algara, M. Sanchez-Beato, A. Sanchez-Aguilera, J. F. Garcia, A. Rodriguez, F. I. Camacho, et al. Somatic hypermutation signature in B-cell low-grade lymphomas Haematologica, August 1, 2008; 93(8): 1186 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dal Col, P. Zancai, L. Terrin, M. Guidoboni, M. Ponzoni, A. Pavan, M. Spina, S. Bergamin, S. Rizzo, U. Tirelli, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma Blood, May 15, 2008; 111(10): 5142 - 5151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Morschhauser, J. F. Seymour, H. C. Kluin-Nelemans, A. Grigg, M. Wolf, M. Pfreundschuh, H. Tilly, J. Raemaekers, M. B. van 't Veer, N. Milpied, et al. A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma Ann. Onc., February 1, 2008; 19(2): 247 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kawamata, J. Chen, and H. P. Koeffler Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells Blood, October 1, 2007; 110(7): 2667 - 2673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Ford, L. Shen, Y. C. Lin-Lee, L. V. Pham, A. Multani, H.-J. Zhou, A. T. Tamayo, C. Zhang, L. Hawthorn, J. K. Cowell, et al. Development of a murine model for blastoid variant mantle-cell lymphoma Blood, June 1, 2007; 109(11): 4899 - 4906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-A. Lyu, L. H. Cheung, W. N. Hittelman, J. W. Marks, R. C.T. Aguiar, and M. G. Rosenblum The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA Mol. Cancer Ther., February 1, 2007; 6(2): 460 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Madoz-Gurpide, P. Lopez-Serra, J. L. Martinez-Torrecuadrada, L. Sanchez, L. Lombardia, and J. I. Casal Proteomics-based Validation of Genomic Data: Applications in Colorectal Cancer Diagnosis Mol. Cell. Proteomics, August 1, 2006; 5(8): 1471 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sanchez-Aguilera, C. Montalban, P. de la Cueva, L. Sanchez-Verde, M. M. Morente, M. Garcia-Cosio, J. Garcia-Larana, C. Bellas, M. Provencio, V. Romagosa, et al. Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma Blood, July 15, 2006; 108(2): 662 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ek, U. Andreasson, S. Hober, C. Kampf, F. Ponten, M. Uhlen, H. Merz, and C. A. K. Borrebaeck From Gene Expression Analysis to Tissue Microarrays: A Rational Approach to Identify Therapeutic and Diagnostic Targets in Lymphoid Malignancies Mol. Cell. Proteomics, June 1, 2006; 5(6): 1072 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ruiz-Ballesteros, M. Mollejo, A. Rodriguez, F. I. Camacho, P. Algara, N. Martinez, M. Pollan, A. Sanchez-Aguilera, J. Menarguez, E. Campo, et al. Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis Blood, September 1, 2005; 106(5): 1831 - 1838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Rubio-Moscardo, J. Climent, R. Siebert, M. A. Piris, J. I. Martin-Subero, I. Nielander, J. Garcia-Conde, M. J. S. Dyer, M. J. Terol, D. Pinkel, et al. Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome Blood, June 1, 2005; 105(11): 4445 - 4454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Martinez, M. Sanchez-Beato, A. Carnero, V. Moneo, J. C. Tercero, I. Fernandez, M. Navarrete, J. Jimeno, and M. A. Piris Transcriptional signature of Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-naive patients Mol. Cancer Ther., May 1, 2005; 4(5): 814 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Ghobrial, D. J. McCormick, S. H. Kaufmann, A. A. Leontovich, D. A. Loegering, N. T. Dai, K. L. Krajnik, M. J. Stenson, M. F. Melhem, A. J. Novak, et al. Proteomic analysis of mantle-cell lymphoma by protein microarray Blood, May 1, 2005; 105(9): 3722 - 3730. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Gong, A. C. Chan, and F. Martin Contributions of Circulatory Dynamics and Cellular Microenvironment in Anti-CD20 mAb Immunotherapy Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 160 - 165. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rodriguez, N. Martinez, F. I. Camacho, E. Ruiz-Ballesteros, P. Algara, J.-F. Garcia, J. Menarguez, T. Alvaro, M. F. Fresno, F. Solano, et al. Variability in the Degree of Expression of Phosphorylated I{kappa}B{alpha} in Chronic Lymphocytic Leukemia Cases With Nodal Involvement Clin. Cancer Res., October 15, 2004; 10(20): 6796 - 6806. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
