Pathobiology of mantle cell lymphoma
- Jennifer R Brown, MD, PhD
Jennifer R Brown, MD, PhD
- Associate Professor
- Harvard Medical School
- Arnold S Freedman, MD
Arnold S Freedman, MD
- Section Editor — Lymphoproliferative Disorders
- Professor of Medicine
- Harvard Medical School
- Jon C Aster, MD
Jon C Aster, MD
- Professor of Pathology
- Harvard Medical School
Mantle cell lymphoma (MCL) is a mature B cell non-Hodgkin lymphoma (NHL) that accounts for approximately 7 percent of adult NHLs in the United States and Europe. While it is often discussed together with the indolent forms of NHL, its behavior is more often that of an aggressive lymphoma. (See "Classification of the hematopoietic neoplasms".)
MCL has been previously referred to as intermediate lymphocytic lymphoma, mantle zone lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation [1,2].
The pathobiology of MCL will be reviewed here. Information regarding the epidemiology, clinical presentation, diagnosis and treatment of MCL is presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma" and "Initial treatment of mantle cell lymphoma".)
CELL OF ORIGIN
Most mantle cell lymphoma (MCL) cases are postulated to derive from naïve pre-germinal center B cells of the mantle zone, while a subset of MCL may originate from marginal zone or peripheral blood memory B cells.
The pre-germinal center ancestry of most MCLs is principally supported by the absence of somatic mutations in the immunoglobulin heavy chain variable region (IgVH) genes, which serve as a marker of germinal center transit . However, several studies have found somatic hypermutation in approximately 20 to 30 percent of MCL cases [3-5]. IGHV3-21 and IGHV4-34 usage was significantly overrepresented in MCLs in these studies. The V3-21 expressing cases were highly associated with expression of the same light chain, IGLV3-19, suggesting that these tumor cells are stimulated by an autoantigen recognized by the Ig formed by pairing of these heavy and light chains .
- Jiang W, Kahn SM, Zhou P, et al. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene 1993; 8:3447.
- Bodrug SE, Warner BJ, Bath ML, et al. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J 1994; 13:2124.
- Walsh SH, Thorsélius M, Johnson A, et al. Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma. Blood 2003; 101:4047.
- Camacho FI, Algara P, Rodríguez A, et al. Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations. Blood 2003; 101:4042.
- Kienle D, Kröber A, Katzenberger T, et al. VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome. Blood 2003; 102:3003.
- Rimokh R, Berger F, Delsol G, et al. Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell lymphomas. Blood 1994; 83:1871.
- Orchard J, Garand R, Davis Z, et al. A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease. Blood 2003; 101:4975.
- Lovec H, Grzeschiczek A, Kowalski MB, Möröy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J 1994; 13:3487.
- Leshchenko VV, Kuo PY, Shaknovich R, et al. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 2010; 116:1025.
- Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 2012; 119:1963.
- Beà S, Valdés-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A 2013; 110:18250.
- Dai B, Grau M, Juilland M, et al. B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma. Blood 2017; 129:333.
- Seto M, Yamamoto K, Iida S, et al. Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation. Oncogene 1992; 7:1401.
- Quintanilla-Martinez L, Davies-Hill T, Fend F, et al. Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis. Blood 2003; 101:3181.
- Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361.
- Raffeld M, Jaffe ES. bcl-1, t(11;14), and mantle cell-derived lymphomas. Blood 1991; 78:259.
- Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362:1417.
- Allinne J, Pichugin A, Iarovaia O, et al. Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of key genes in mantle cell lymphoma. Blood 2014; 123:2044.
- Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood 2007; 109:4599.
- Chen RW, Bemis LT, Amato CM, et al. Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma. Blood 2008; 112:822.
- Shakir R, Ngo N, Naresh KN. Correlation of cyclin D1 transcript levels, transcript type and protein expression with proliferation and histology among mantle cell lymphoma. J Clin Pathol 2008; 61:920.
- Gelebart P, Anand M, Armanious H, et al. Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma. Blood 2008; 112:5171.
- Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 2003; 3:185.
- Fu K, Weisenburger DD, Greiner TC, et al. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood 2005; 106:4315.
- Salaverria I, Royo C, Carvajal-Cuenca A, et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma. Blood 2013; 121:1394.
- Swerdlow SH, Campo E, Harris NL, et al. (Eds). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
- Pinyol M, Hernandez L, Cazorla M, et al. Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas. Blood 1997; 89:272.
- Stefancikova L, Moulis M, Fabian P, et al. Loss of the p53 tumor suppressor activity is associated with negative prognosis of mantle cell lymphoma. Int J Oncol 2010; 36:699.
- Espinet B, Salaverria I, Beà S, et al. Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma. Genes Chromosomes Cancer 2010; 49:439.
- Ek S, Dictor M, Jerkeman M, et al. Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood 2008; 111:800.
- Nygren L, Baumgartner Wennerholm S, Klimkowska M, et al. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood 2012; 119:4215.
- Vegliante MC, Palomero J, Pérez-Galán P, et al. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood 2013; 121:2175.
- Palomero J, Vegliante MC, Rodríguez ML, et al. SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma. Blood 2014; 124:2235.
- Greiner TC, Dasgupta C, Ho VV, et al. Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. Proc Natl Acad Sci U S A 2006; 103:2352.
- Greiner TC, Moynihan MJ, Chan WC, et al. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 1996; 87:4302.
- Stilgenbauer S, Schaffner C, Winkler D, et al. The ATM gene in the pathogenesis of mantle-cell lymphoma. Ann Oncol 2000; 11 Suppl 1:127.
- Hofmann WK, de Vos S, Tsukasaki K, et al. Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray. Blood 2001; 98:787.
- Menendez P, Vargas A, Bueno C, et al. Quantitative analysis of bcl-2 expression in normal and leukemic human B-cell differentiation. Leukemia 2004; 18:491.
- Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005; 9:59.
- Srinivasan L, Sasaki Y, Calado DP, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 2009; 139:573.
- Rudelius M, Pittaluga S, Nishizuka S, et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 2006; 108:1668.
- Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369:507.
- Pham LV, Tamayo AT, Yoshimura LC, et al. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 2003; 171:88.
- Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Nat Med 2014; 20:87.
- Fernàndez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 2010; 70:1408.
- Iqbal J, Shen Y, Liu Y, et al. Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis. Blood 2012; 119:4939.
- Navarro A, Clot G, Prieto M, et al. microRNA expression profiles identify subtypes of mantle cell lymphoma with different clinicobiological characteristics. Clin Cancer Res 2013; 19:3121.
- Tiemann M, Schrader C, Klapper W, et al. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol 2005; 131:29.
- Determann O, Hoster E, Ott G, et al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood 2008; 111:2385.