Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. 13q14 deletions are most common chromosomal alterations in CLL. We previously reported that miR-15/16 is a target of 13q14 deletions and plays a tumor suppressor role by targeting BCL2. Because DLEU7 is located near miR-15/16 and is also positioned within a minimal deleted region, we investigated whether DLEU7 could also play a tumor suppressor role. Recent studies of transgenic mouse models demonstrated the importance of the nuclear factor-kappaB (NF-kappaB) pathway in CLL. To examine the possible role of DLEU7 in CLL, we investigated the effect of DLEU7 expression on NF-kappaB and nuclear factor of activated T cells (NFAT) activity. We found that DLEU7 functions as a potent NF-kappaB and NFAT inhibitor by physically interacting and inhibiting TACI and BCMA, members of the tumor necrosis factor (TNF) receptor family involved in B-CLL. In addition, DLEU7 expression in A549 lung cancer cells resulted in a decrease in S phase and increased apoptosis. The results suggest that loss of DLEU7 may cooperate with the loss of miR-15/16 in the pathogenesis of CLL.
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PMID:13q14 deletions in CLL involve cooperating tumor suppressors. 2046 68

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, results from an expansion of a rare population of CD5+ mature B-lymphocytes. CLL occurs in two forms, aggressive and indolent. For the most part indolent CLL is characterized by low ZAP-70 expression and mutated IgH V(H); aggressive CLL shows high ZAP-70 expression and unmutated IgH V(H). Although clinical features and genomic abnormalities in CLL have been studied extensively, molecular mechanisms underlying disease development are still emerging. In the last few years, several important insights were reported in this area. MiR-15/16 targeting BCL2 and MCL1 and DLEU7 targeting TNF pathway were proposed as tumor suppressors at 13q14, a commonly deleted region in indolent CLL. Molecular details of how activation of TCL1, a critical oncogene in aggressive CLL, results in the initiation of this malignancy were clarified. Importance of these pathways was supported by investigations of several mouse models of CLL. Here, we present what has been learned from these new pathways, discuss mouse CLL models and how these mouse models recapitulate the molecular mechanisms of this common leukemia.
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PMID:Molecular basis of CLL. 2086 94

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 V(H), while indolent CLL is characterized by low ZAP-70 expression and mutated IgH V(H). 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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PMID:Novel insights in molecular mechanisms of CLL. 2259 86