Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia

Cobo, Francesc; Martı́nez, Antonio; Pinyol, Magda; Hernández, Lluís; Gómez, Marta; Beà, Sı́lvia; Esteve, Jordi; Rozman, Marı́a; Bosch, Francesc; López‐Guillermo, Armando; Montserrat, Emili; Campo, Elı́as

doi:10.1038/sj.leu.2402529

Cited by 31 publications

(29 citation statements)

References 47 publications

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“…An increasing number of p53-positive cases was found when comparing patients with "nonaccelerated" CLL to those with "accelerated" CLL and to those with DLBCL-t. Although the high frequency of p53 alterations has been extensively recognized in DLBCL transformation, 35,36 the relative small number of cases in the latter two subsets precludes any definitive conclusion.…”

Section: Discussionmentioning

confidence: 93%

Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior

Giné

Martı́nez²,

Villamor³

et al. 2010

Haematologica

163

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BackgroundThe concept of "accelerated" chronic lymphocytic leukemia is frequently used by both pathologists and clinicians. However, neither histological criteria to define this form of chronic lymphocytic leukemia nor its clinical correlates and prognostic impact have been formally defined in large series of patients. Design and MethodsTissue biopsies from 100 patients with chronic lymphocytic leukemia were analyzed for the size of proliferation centers and their proliferation rate as assessed by mitosis count and Ki-67 immunostaining. Histological patterns were correlated with main clinico-biological features and outcome. ResultsA suspicion of disease transformation was the main reason for carrying out tissue biopsy, which was performed at a median time of 14 months (range, 0 to 204 months) after the diagnosis of chronic lymphocytic leukemia. The biopsy showed histological transformation to diffuse large B-cell lymphoma in 22 cases. In the remaining 78 patients, the presence of expanded proliferation centers (broader than a 20x field) and high proliferation rate (either >2.4 mitoses/proliferation center or Ki-67 >40%/proliferation center) predicted a poor outcome and were selected to define a highly proliferative group. Thus, 23 patients with either expanded proliferation centers or high proliferation rate were considered as having "accelerated" chronic lymphocytic leukemia. These patients displayed particular features, including higher serum lactate dehydrogenase levels and more frequently elevated ZAP-70 than "non-accelerated" cases. The median survival from biopsy of patients with "non-accelerated" chronic lymphocytic leukemia, "accelerated" chronic lymphocytic leukemia and transformation to diffuse large Bcell leukemia was 76, 34, and 4.3 months, respectively (P<0.001). ConclusionsThe presence of expanded and/or highly active proliferation centers identifies a group of patients with "accelerated" chronic lymphocytic leukemia characterized by an aggressive clinical behavior.Key words: accelerated chronic lymphocytic leukemia, lymph node biopsy, ZAP-70. Haematologica 2010;95(9):1526-1533. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Giné E, MartinezExpanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior

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Section: Discussionmentioning

confidence: 93%

Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior

Giné

Martı́nez²,

Villamor³

et al. 2010

Haematologica

163

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“…Cyclin D1 and D3 levels have been reported to be higher in leukemic cells than in normal circulating B cells (43). In addition, increased levels of cyclin D1 were reported in CD5 + zap70 + CLL cells as compared with CD5 + zap70 − CLL cells (44), as well as in a subset of patients with clinically aggressive CLL (45). Our New Zealand Black-derived malignant B-1 cell line, LNC, mimics late-stage aggressive CLL (27).…”

Section: Discussionmentioning

confidence: 99%

Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity

Salerno

Scaglione

Coffman

et al. 2009

Molecular Cancer Therapeutics

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Alterations in the human 13q14 genomic region containing microRNAs mir-15a and mir-16-1 are present in most human chronic lymphocytic leukemia (CLL). We have previously found the development of CLL in the New Zealand Black murine model to be associated with a point mutation in the primary mir-15a/16-1 region, which correlated with a decrease in mature miR-16 and miR-15a levels. In this study, addition of exogenous miR-15a and miR-16 led to an accumulation of cells in G 1 in non-New Zealand Black B cell and New Zealand Black-derived malignant B-1 cell lines. However, the New Zealand Black line had significantly greater G 1 accumulation, suggesting a restoration of cell cycle control upon exogenous miR-15a/16 addition. Our experiments showed a reduction in protein levels of cyclin D1, a miR-15a/16 target and cell cycle regulator of G 1 /S transition, in the New Zealand Black cell line following miR-15a/16 addition. These microRNAs were shown to directly target the cyclin D1 3′ untranslated region using a green fluorescent protein lentiviral expression system. miR-16 was also shown to augment apoptosis induction by nutlin, a mouse double minute 2 (MDM2) antagonist, and genistein, a tyrosine kinase inhibitor, when added to a B-1 cell line derived from multiple in vivo passages of malignant B-1 cells from New Zealand Black mice with CLL. miR-16 synergized with nutlin and genistein to induce apoptosis. Our data support a role for the mir-15a/ 16-1 cluster in cell cycle regulation and suggest that these mature microRNAs in both the New Zealand Black model and human CLL may be targets for therapeutic efficacy in this disease. [Mol Cancer Ther 2009;8(9):2684-92]

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“…Indeed, previous studies have extensively documented that p27(Kip1) expression or distribution is frequently abnormal in lymphoid neoplasias, including advanced B-CLL, mantle cell lymphoma, or diffuse large cell lymphoma. [45][46][47] To conclude, our study suggests that rituximab induced a complex signaling pathway consisting in the stimulation of an intracellular Zn 2ϩ -independant A-SMase followed by the translocation of the active form of this enzyme to plasma membrane raft microdomains and hydrolysis of the outer leaflet-associated SM. CER issued from SM hydrolysis facilitates the recruitment of MAPK components in lipid microdomains and thus could be a critical intermediate of the cellular response to rituximab by linking CD20 activation and MAPK-mediated downstream effector signaling.…”

Section: Discussionmentioning

confidence: 99%

Rituximab antiproliferative effect in B-lymphoma cells is associated with acid-sphingomyelinase activation in raft microdomains

Bezombes

Grazide²,

Garret³

et al. 2004

Blood

118

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Rituximab is a chimeric human immunoglobulin G1 (IgG1) anti-CD20 monoclonal antibody with significant activity against CD20 ؉ malignant B cells. Rituximab is currently used with success in the treatment of B-cell-derived lymphoid neoplasias either alone or in combination with chemotherapy. However, the predominant mechanism by which rituximab exerts its antitumor properties in vivo remains unknown. In the present study, we demonstrate that in Daudi and RL B-lymphoma cells, rituximab (without cross-linking) used at the saturating dose of 10 g/mL induced moderate accumulation in G 1 phase, growth inhibition, and significant loss in clonogenic potential. However, in these cells, rituximab induced no apoptosis. Furthermore, we observed that treatment with rituximab resulted in a rapid and transient increase in acid-sphingomyelinase (A-SMase) activity and concomitant cellular ceramide (CER) generation in raft microdomains. We also observed that rituximab-treated cells externalized both A-SMase and CER that colocalized with the CD20 receptor. Finally, we present evidence that rituximab-induced growth inhibition may be mediated through a CER-triggered signaling pathway, leading to the induction of cell cycle-dependent kinase inhibitors such as p27(Kip1) through a mitogenactivated protein kinase (MAPK)-dependent

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Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia

Abstract: To investigate the role of the cell cycle regulators p21 Waf1 , p27 Kip1

Cited by 31 publications

References 47 publications

Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior

Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior

Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity

Rituximab antiproliferative effect in B-lymphoma cells is associated with acid-sphingomyelinase activation in raft microdomains

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