Abstract
B-cell chronic lymphocytic leukemia (CLL), the most common leukemia, originates from an expansion of a rare population of CD5+CD19+ mature B-cells. CLL occurs in two forms, aggressive and indolent. For the most part aggressive CLL shows high ZAP-70 expression and unmutated IgH VH, while indolent CLL is characterized by low ZAP-70 expression and mutated IgH VH. Despite detailed studies of clinical features and chromosomal abnormalities in CLL, molecular details underlying disease development are still not entirely clear. In the past several years, more and more such mechanisms have emerged. Recent studies clarified mechanistic details of how activation of TCL1, a critical molecule in aggressive CLL, initiates this malignancy. In indolent CLL characterized by 13q14 deletions, MiR-15/16 targeting BCL2 and MCL1 and DLEU7 targeting TNF pathway were proposed as tumor suppressors. Analysis of CLL coding genome identified NOTCH1 as a frequent target of activating mutations. Interestingly most of these pathways have downstream activating effects on the NF-kB family transcription factors. Several mouse models of CLL, confirmed importance of these pathways in the pathogenesis of CLL. Here, we discuss what has been learned from these new pathways, and analyze how CLL mouse models confirm newly discovered molecular mechanisms of CLL.
Keywords: CLL, TCL1, miR-15/16, miR-29, DLEU7, NOTCH1, mature B-cells, ZAP-70 expression, mutations, transcription factors
Current Pharmaceutical Design
Title:Novel Insights in Molecular Mechanisms of CLL
Volume: 18 Issue: 23
Author(s): Nicola Zanesi, Veronica Balatti, Arianna Bottoni, Carlo M. Croce and Yuri Pekarsky
Affiliation:
Keywords: CLL, TCL1, miR-15/16, miR-29, DLEU7, NOTCH1, mature B-cells, ZAP-70 expression, mutations, transcription factors
Abstract: B-cell chronic lymphocytic leukemia (CLL), the most common leukemia, originates from an expansion of a rare population of CD5+CD19+ mature B-cells. CLL occurs in two forms, aggressive and indolent. For the most part aggressive CLL shows high ZAP-70 expression and unmutated IgH VH, while indolent CLL is characterized by low ZAP-70 expression and mutated IgH VH. Despite detailed studies of clinical features and chromosomal abnormalities in CLL, molecular details underlying disease development are still not entirely clear. In the past several years, more and more such mechanisms have emerged. Recent studies clarified mechanistic details of how activation of TCL1, a critical molecule in aggressive CLL, initiates this malignancy. In indolent CLL characterized by 13q14 deletions, MiR-15/16 targeting BCL2 and MCL1 and DLEU7 targeting TNF pathway were proposed as tumor suppressors. Analysis of CLL coding genome identified NOTCH1 as a frequent target of activating mutations. Interestingly most of these pathways have downstream activating effects on the NF-kB family transcription factors. Several mouse models of CLL, confirmed importance of these pathways in the pathogenesis of CLL. Here, we discuss what has been learned from these new pathways, and analyze how CLL mouse models confirm newly discovered molecular mechanisms of CLL.
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Cite this article as:
Zanesi Nicola, Balatti Veronica, Bottoni Arianna, M. Croce Carlo and Pekarsky Yuri, Novel Insights in Molecular Mechanisms of CLL, Current Pharmaceutical Design 2012; 18 (23) . https://dx.doi.org/10.2174/138161212801227104
DOI https://dx.doi.org/10.2174/138161212801227104 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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