Five-Gene Model to Predict Survival in Mantle-Cell Lymphoma Using Frozen or Formalin-Fixed, Paraffin-Embedded Tissue

Hartmann, Elena; Fernández, Verónica; Moreno, Vı́ctor; Valls, Joan; Hernández, Luís; Bosch, Francesc; Abrisqueta, Pau; Klapper, Wolfram; Dreyling, Martin; Hoster, Eva; Müller‐Hermelink, Hans Konrad; Ott, German; Rosenwald, Andreas; Campo, Elı́as

doi:10.1200/jco.2007.12.0410

Cited by 101 publications

(62 citation statements)

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“…In addition to the translocation and overexpression of cyclin D1, a number of other genetic and nongenetic alterations resulting in deregulated cell cycle progression and/or reduced apoptosis have been reported in MCLs. 1,10,11,40,43,44,48,49 In that line, pharmacological inhibitors of Wnt signaling or knockdown of components of the pathway reduce proliferation and trigger apoptosis in MCL cells. 5,6 Our data show that ZEB1 could have a role in the regulation of proliferation and apoptosis in MCL.…”

Section: Discussionmentioning

confidence: 99%

“…40,48,49 In addition to Ki-67, traditionally used in clinical applications, 48 gene and protein expression analyses in primary MCLs have identified different markers associated to proliferation that independently or jointly serve as predictors of worse prognosis in MCL. 40,48,49 We therefore explored The EMT activator ZEB1 in MCL E Sánchez-Tilló et al whether ZEB1 expression associates to proliferationassociated genes. Indeed, ZEB1 was positively correlated with the proliferation signature average defined by Rosenwald et al 40 , a number of genes included in that signature (HMGB2, UHRF1, and CENPF), as well as well-known proliferationrelated genes like MYC and MKI67 (Supplementary Table S1).…”

Section: H-thymidine and Brdu Incorporation (Figures 4b And C)mentioning

confidence: 99%

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The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

et al. 2013

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Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a poor response to treatment and prognosis. Constitutive activation of different signaling pathways in subsets of MCLs, through genetic and/or nongenetic alterations, endows tumor cells with enhanced proliferation and reduced apoptosis. The canonical Wnt pathway (b-catenin/TCF-LEF), implicated in the pathogenesis of numerous cancers, is constitutively active in half of MCLs. Here, we show that ZEB1, a transcription factor better known for promoting metastasis in carcinomas, is expressed in primary MCLs with active Wnt signaling. ZEB1 expression in MCL cells depends on Wnt, being downregulated by b-catenin knockdown or blocking of Wnt signaling by salinomycin. Knockdown of ZEB1 reduces in vitro cell viability and proliferation in MCL cells, and, importantly, tumor growth in mouse xenograft models. ZEB1 activates proliferation-associated (HMGB2, UHRF1, CENPF, MYC, MKI67, and CCND1) and antiapoptotic (MCL1, BCL2, and BIRC5) genes and inhibits pro-apoptotic ones (TP53, BBC3, PMAIP1, and BAX). We show that ZEB1 expression in MCL cells determines differential resistance to chemotherapy drugs and regulates transporters involved in drug influx/efflux. Downregulation of ZEB1 by salinomycin increases the sensitivity of MCL cells to the cytotoxic effect of doxorubicin, cytarabine and gemcitabine. Lastly, salinomycin and doxorubicin display a synergistic effect in established and primary MCL cells. These results identify ZEB1 in MCL where it promotes cell proliferation, enhanced tumor growth and a differential response to chemotherapy drugs. ZEB1 could thus potentially become a predictive biomarker and therapeutic target in this lymphoma.

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Section: Discussionmentioning

confidence: 99%

Section: H-thymidine and Brdu Incorporation (Figures 4b And C)mentioning

confidence: 99%

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

et al. 2013

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“…However, a microarray-based technique is not feasible on a wide scale. Therefore, further testing of a minimum number of genes by formalin-fixed, paraffin-embedded tissue specimens has been studied [24]. This study identified five genes including RAN, MYC, TNFRSF10B, POLE2, and SLC29A2 which were …”

Section: Risk Stratificationmentioning

confidence: 99%

Mantle cell lymphoma: 2015 update on diagnosis, risk‐stratification, and clinical management

Vose

2015

American J Hematol

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Disease Overview: Mantle cell lymphoma (MCL) is a non‐Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4‐5 years.Diagnosis: Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX‐11 or a low Ki‐67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma.Risk Stratification: The MCL International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki‐67 proliferative index if available. The median OS for the low‐risk group was not reached (5‐year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group.Risk‐Adapted Therapy: For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytotoxic regimen ± autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R‐CHOP, R‐Bendamustine, or a clinical trial should be considered. In addition, rituximab maintenance therapy may prolong the progression‐free survival. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), lenalidamide (anti‐angiogenesis) and Ibruitinib (Bruton's Tyrosine Kinase [BTK] inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients. Clinical trials with novel agents are always a consideration for MCL patients. Am. J. Hematol. 90:740–745, 2015. © 2015 Wiley Periodicals, Inc.

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“…The majority of genes associated with outcome in MCL are expressed in a proliferation-dependent manner (27). This proliferation signature was later used as a basis for the development of a quantitative PCR assay successfully applied to FFPE tissue (57). Another 26-gene expression signature also showed prognostic significance, but, similar to the PCR-based assay, incorporated additional proliferation-independent genes (42).…”

Section: Gene Expression Profilingmentioning

confidence: 99%

New Paradigms in Mantle Cell Lymphoma: Is It Time to Risk-Stratify Treatment Based on the Proliferative Signature?

Dreyling

Ferrero

Vogt

et al. 2014

Clinical Cancer Research

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The elucidation of crucial biologic pathways of cell survival and proliferation has led to the development of highly effective drugs, some of which have markedly improved mantle cell lymphoma (MCL) therapeutic opportunities in the past 10 years. Moreover, an undeniable clinical heterogeneity in treatment response and disease behavior has become apparent in this neoplasm. Thus, the need for biologic markers stratifying patients with MCL in risk classes deserving different treatment approaches has recently been fervently expressed. Among several newly discovered biomarkers, the dismal predictive value of a high proliferative signature has been broadly recognized in large studies of patients with MCL. Different techniques have been used to assess tumor cell proliferation, including mitotic index, immunostaining with Ki-67 antibody, and gene expression profiling. Ki-67 proliferative index, in particular, has been extensively investigated, and its negative impact on relapse incidence and overall survival has been validated in large prospective clinical trials. However, one important pitfall limiting its widespread use in clinical practice is the reported interobserver variability, due to the previous lack of a standardized approach for quantification among different laboratories. In the present review, we describe some of the major techniques to assess cell proliferation in MCL, focusing in particular on the Ki-67 index and its need for a standardized approach to be used in multicenter clinical trials. The value of MCL biologic prognostic scores (as MIPI-b) is discussed, along with our proposal on how to integrate these scores in the planning of future trials investigating a tailored therapeutic approach for patients with MCL.

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Five-Gene Model to Predict Survival in Mantle-Cell Lymphoma Using Frozen or Formalin-Fixed, Paraffin-Embedded Tissue

Abstract: We here present a validated qRT-PCR-based test for survival prediction in patients with MCL that is applicable to fresh frozen as well as to FFPE tissue specimens. This test may prove useful to guide individualized treatment approaches for patients with MCL.

Cited by 101 publications

References 51 publications

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

Mantle cell lymphoma: 2015 update on diagnosis, risk‐stratification, and clinical management

New Paradigms in Mantle Cell Lymphoma: Is It Time to Risk-Stratify Treatment Based on the Proliferative Signature?

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