Molecular pathogenesis of mantle cell lymphoma

Abstract

Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. IntroductionMantle cell lymphoma (MCL) is a B cell malignancy with a broad spectrum of clinical, pathological, and biological features. The identification of the translocation event t(11;14)(q13;q32) and the resulting cyclin D1 overexpression were of paramount importance in recognizing the clinical and biological diversity of this tumor. In addition to this constitutive dysregulation of the cell cycle, other mechanisms such as DNA damage response alterations and activation of cell survival pathways are integrated to drive MCL pathogenesis (1, 2). New observations are expanding our views on the ontogeny and pathogenesis of this lymphoma. Furthermore, these new insights into MCL oncogenesis are promoting the development of new therapeutic strategies, intended to target the molecular mechanism of the disease, and opening up new clinical perspectives for optimal diagnosis and management of the patients.

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

“…1 MCLs derive from naive B cells displaying a mature phenotype similar to those in the mantle zone of lymph node follicles. Evidence at multiple levels indicates that MCL is a more heterogeneous entity than previously thought.…”

“…Evidence at multiple levels indicates that MCL is a more heterogeneous entity than previously thought. 1 The genetic hallmark of MCLs is the t(11;14)(q13;q32) translocation of cyclin D1 to the Ig heavy chain enhancer. However, cyclin D1 overexpression is not sufficient to induce MCL in mice, its knockdown has limited effect on the proliferation or apoptosis of MCL cells and cyclin D1-negative cases have also been identified.…”

“…However, cyclin D1 overexpression is not sufficient to induce MCL in mice, its knockdown has limited effect on the proliferation or apoptosis of MCL cells and cyclin D1-negative cases have also been identified. 1,2 Clinical, pathological and ontogenic heterogeneity among subsets of MCLs reflect the involvement of additional signals in the genesis and evolution of this lymphoma. In that regard, chromosomal alterations and nongenetic modifications resulting in the constitutive activation of pro-oncogenic signals (for example, NF-kB, Notch, PI3K/AKT/mTOR, and Wnt) and/or deregulation of DNA repair and apoptotic pathways and genes (for example, AKT, BCL2, MCL1) have been found in subsets of MCLs, providing additional levels of plasticity in the genesis and progression of the disease.…”

“…In that regard, chromosomal alterations and nongenetic modifications resulting in the constitutive activation of pro-oncogenic signals (for example, NF-kB, Notch, PI3K/AKT/mTOR, and Wnt) and/or deregulation of DNA repair and apoptotic pathways and genes (for example, AKT, BCL2, MCL1) have been found in subsets of MCLs, providing additional levels of plasticity in the genesis and progression of the disease. 1,[3][4][5][6][7][8][9][10][11] Of particular interest is the canonical Wnt pathway that has a crucial role in normal hematopoiesis and whose aberrant activation, long known to drive tumorigenesis in solid tumors, has also been involved in a number of hematological malignancies, including MCLs. 3,5,6,[12][13][14][15][16][17][18][19]20 In addition to gain-of-function mutations of intracellular components of the Wnt pathway, overexpression of Wnt receptors and ligands or downregulation of Wnt inhibitors through nongenetic modifications are also common.…”

“…3,[5][6][7]21 Short-lived response and development of resistance to first-line immunochemotherapy are major challenges in MCL and new therapeutic strategies are being developed. 1,22,23 Constitutive Wnt signaling associates to increased cellular proliferation and higher resistance to apoptosis and chemotherapy in subsets of leukemias and lymphomas and established cell lines derived from them, including MCLs. 3,5,6,13,[15][16][17][18][19][20] In turn, inhibitors of Wnt pathway induce cytotoxicity in leukemia and lymphoma cells.…”