Cell cycle deregulation in B-cell lymphomas

Abstract

Disruption of the physiologic balance between cell proliferation and death is a universal feature of all cancers. In general terms, human B-cell lymphomas can be subdivided into 2 main groups, low-and high-growth fraction lymphomas, according to the mechanisms through which this imbalance is achieved. Most types of low-growth fraction lymphomas are initiated by molecular events resulting in the inhibition of apoptosis, such as translocations affecting BCL2, in follicular lymphoma, or BCL10 and API2/MLT1, in mucosa-associated lymphoid tissue (MALT) lymphomas. This results in cell accumulation as a consequence of prolonged cell survival. In contrast, high-growth fraction lymphomas are characterized by an enhanced proliferative activity, as a result of the deregulation of oncogenes with cell cycle regulatory functions, such as BCL6, in large B-cell lymphoma, or c-myc, in Burkitt lymphoma. Low-and high-growth fraction lymphomas are both able to accumulate other alterations in cell cycle regulation, most frequently involving tumor suppressor genes such as p16 INK4a , p53, and p27 KIP1 . As a consequence, these tumors behave as highly aggressive lymphomas. The simultaneous inactivation of several of these regulators confers increased aggressivity and proliferative advantage to tumoral cells. In this review we discuss our current knowledge of the alterations in each of these pathways, with special emphasis on the deregulation of cell cycle progression, in an attempt to integrate the available information within a global model that describes the contribution of these molecular changes to the genesis and progression of B-cell lymphomas. IntroductionAlthough studies in experimental models and analyses of virusinduced cell transformation have shown that cell cycle subversion is a key step in tumorigenesis, the available information on human tumors has only recently reached the critical threshold of knowledge that allows a reasonably clear understanding of the mechanisms of cell cycle inactivation and their contribution to the genesis and progression of human cancer. Here, we have chosen B-cell lymphoproliferative lesions on the understanding that the accumulation of data concerning alterations in specific key genes makes it possible to propose a general model that describes the role of these specific alterations in cell cycle regulators in the initiation and progression of these tumors.Lymphoma/leukemia is a group of different types of cancer of the lymphoid system, in which numerous entities feature distinctive molecular alterations (Table 1). The most frequent types of lymphoma are collectively denominated B-cell lymphomas (BCLs), a term that encompasses different entities with variable clinical behavior and diverse molecular features. Nevertheless, in general terms, it is possible to segregate BCLs into 2 main groups, defined as low-and high-growth fraction lymphomas that roughly overlap with previous definitions of low-and high-histologic grade.Low-growth fraction BCLs, including follicular lymphoma (FL), marginal zo...

Nuclear bcl10 expression characterizes a group of ocular adnexa MALT lymphomas with shorter failure-free survival

“…12,15,[31][32][33]35 The nuclear expression of bcl10 has been proposed as a surrogate of NF-kB activation after (11;18)(q21;q21), t(1;14)(p22;q32), while strong cytoplasmic expression has been linked with t(14;18)(q32;q21). 7,12,22,35,36 Strikingly, our data show a clear association between nuclear bcl10, increased expression of p-IkBa, and shorter time to failure. This, in addition to providing predictor parameters, suggests tentative therapeutic targets.…”

“…IkB-a is a physiological ligand of NF-kB in the cytoplasm, whose phosphorylation permits the liberation and migration of NF-kB into the nucleus, where NF-kB plays its transcriptional role, upregulating the expression of antiapoptotic proteins. 7,[27][28][29][30] In MALT lymphoma, deregulation of the expression of MALT1 gene due to chromosomal translocations t(11;18)(q21; q21) and t(14;18)(q32;q21) seems to be one of the main pathogenic mechanisms leading to reduced apoptotic activity. 12,15,22,[31][32][33] In contrast to what has been described in gastric MALT lymphomas, our results did not indicate the presence of t (11;18).…”

“…[1][2][3][4][5][6] Lymphomagenesis is driven by multiple accumulated genetic abnormalities that determine the survival of neoplastic cells and involve mainly cell-cycle and apoptotic pathways. 7 MALT lymphomas in particular are a paradigm of alternative genetic events, involving different chromosomal aberration and/or apoptosis control protein expression, leading to the deregulation of apoptotic pathways through the activation of the NF-kB pathway. 7,8 In general, MALT lymphomas at different extranodal locations share some common morphological, phenotypic and molecular features, which has led to the establishment of gastric MALT lymphoma as the prototype for the definition of the features of MALT lymphoma at different sites.…”

“…7 MALT lymphomas in particular are a paradigm of alternative genetic events, involving different chromosomal aberration and/or apoptosis control protein expression, leading to the deregulation of apoptotic pathways through the activation of the NF-kB pathway. 7,8 In general, MALT lymphomas at different extranodal locations share some common morphological, phenotypic and molecular features, which has led to the establishment of gastric MALT lymphoma as the prototype for the definition of the features of MALT lymphoma at different sites. 9,10 Nevertheless, there is increasing evidence to suggest that cases diagnosed with MALT lymphomas arising at different sites differ in the presence of infectious specific antigens-Helicobacter, Campylobacter, Borrelia, Chlamydia-promoting lymphoid cell proliferation, and in the frequency of chromosomal translocations such as t(11;18)(q21;q21), or the newly described t(14;18)(q32;q21) and t(3;14) (p14.1;q32).…”

Retinoblastoma gene family expression in lymphoid tissues

“…Levels of pRb/p105 are low in low-growth fraction non-Hodgkin's lymphomas (NHLs), whereas they are higher in most high-growth fraction tumours (Sanchez-Beato et al, 2003). A positive correlation between the expression of p107 and proliferative features such as mitotic index and percentage of Ki67 and cyclin A cells has also been demonstrated in a large series of NHL, whereas such a correlation could not be demonstrated for the percentages of pRb2/p130-positive cells (Leoncini et al, 1999).…”