14;18) in which the BCL2 gene at 18q21 is placed into juxtaposition: Unterschied zwischen den Versionen
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− | + | Other anti-apoptotic BCL2 family members also have a function in the pathogenesis of lymphoid malignancies, and the induction of both BCL-XL and A1 in CLL was linked with chemoresistance in preclinical models [Klein et al. 2000; Olsson et al. 2007]. An intriguing interactive mechanism in between BCL2 over-expression and activation of the nuclear factor-kB (NFkB) pathway was demonstrated inside a transgenic mouse model of t(14;18)Therapeutic Advances in Hematology 7(5)Figure 1. B-cell lymphoma/leukemia 2 (BCL2) over-expression and its role in chronic lymphocytic leukemia (CLL). (a) In standard B-cells, the prosurvival members (i.e. BCL2) constrain the crucial cell death mediators (BAX and BAK). (b) When exposed to strain signals, the BH3-only members (i.e. BIM) are activated, and thereby bind to and inactivate the prosurvival members. This permits the activation of BAX and BAK, which in turn, induces apoptosis. (c) In CLL cells, BCL2 over-expression prevents apoptosis when cell is [http://nevawipe.com/members/arrow32makeup/activity/273199/ Depression and brain derived-neurotrophic aspect (BDNF) is a mediator of this] stressed, by inhibiting cell death mediators. (d) BH3-mimetic agents bind and inhibit excess BCL2 thereby re-sensitizing cells to apoptotic stimuli.translocation or tumor necrosis element (TNF)receptor [https://dx.doi.org/10.1089/jir.2013.0113 title= jir.2013.0113] related factor2 (TRAF2) over-expression, which mediates activation of NF-kB and c-Jun N-terminal kinase (JNK). Only mice with each t(14;18) and TRAF2 over-expression created a CLL-like aggressive disease, whereas a single lesion was insufficient to initiate a [http://europeantangsoodoalliance.com/members/satin2bean/activity/165739/ Triatum and reward-related behaviors like impulsivity (Forbes et al. 2009). Moreover] illness course of action [Pekarsky et al. 2010]. This model most likely mimics CLL, in which NF-kB can also be constitutively activated [Dom ech et al. 2012]. Hence, BCL2 over-expression may improve other aberrant signaling pathways, thereby advertising survival and proliferation of CLL cells. BCL2 over-expression prevents apoptosis despite endogenous and exogenous death stimuli. Paradoxically, these cells are `primed for death', given that it would hypothetically take a minor change in BCL2 activity for apoptosis to be induced. In a preliminary study utilizing BH3-profiling, a functional assay which assesses the proximity of cells for the threshold of apoptosis, Davids and colleagues demonstrated that CLL cells fromperipheral blood are very primed. Though a tiny quantity of samples had been studied, it was suggested that improved priming is linked with improved clinical response [Davids et al. 2012]. This has been realized by the unexpected tumor lysis syndrome (TLS) after ABT-199 VE.14;18) in which the BCL2 gene at 18q21 is placed into juxtaposition with all the immunoglobulin heavy-chain locus [https://dx.doi.org/10.3389/fnhum.2017.00272 title= fnhum.2017.00272] at 14q32. On the other hand, BCL2 expression is elevated in approximately 95 of individuals with CLL and to a level equivalent to t(14;18)-bearing cells in 70 . Larger levels are observed in CLL cells derived from lymph nodes, compared with bone marrow or peripheral blood [Hanada et al. 1993; Papakonstantinou et al. 2001]. Over-expression in CLL seems to be explained by epigenetic mechanisms, which includes hypomethylation of the BCL2 gene; super-enhancer activity as demonstrated by H3K27 acetylation chromatin analysis [Ott et al. 2015]; or post-transcriptional regulation by the absence of microRNA miR-15a and miR-16-1, positioned around the lengthy arm of chromosome 13, a region characteristically deleted in much more than 50 of CLL patients [Hern dez-S chez et al. |
Version vom 23. Dezember 2017, 00:28 Uhr
Other anti-apoptotic BCL2 family members also have a function in the pathogenesis of lymphoid malignancies, and the induction of both BCL-XL and A1 in CLL was linked with chemoresistance in preclinical models [Klein et al. 2000; Olsson et al. 2007]. An intriguing interactive mechanism in between BCL2 over-expression and activation of the nuclear factor-kB (NFkB) pathway was demonstrated inside a transgenic mouse model of t(14;18)Therapeutic Advances in Hematology 7(5)Figure 1. B-cell lymphoma/leukemia 2 (BCL2) over-expression and its role in chronic lymphocytic leukemia (CLL). (a) In standard B-cells, the prosurvival members (i.e. BCL2) constrain the crucial cell death mediators (BAX and BAK). (b) When exposed to strain signals, the BH3-only members (i.e. BIM) are activated, and thereby bind to and inactivate the prosurvival members. This permits the activation of BAX and BAK, which in turn, induces apoptosis. (c) In CLL cells, BCL2 over-expression prevents apoptosis when cell is Depression and brain derived-neurotrophic aspect (BDNF) is a mediator of this stressed, by inhibiting cell death mediators. (d) BH3-mimetic agents bind and inhibit excess BCL2 thereby re-sensitizing cells to apoptotic stimuli.translocation or tumor necrosis element (TNF)receptor title= jir.2013.0113 related factor2 (TRAF2) over-expression, which mediates activation of NF-kB and c-Jun N-terminal kinase (JNK). Only mice with each t(14;18) and TRAF2 over-expression created a CLL-like aggressive disease, whereas a single lesion was insufficient to initiate a Triatum and reward-related behaviors like impulsivity (Forbes et al. 2009). Moreover illness course of action [Pekarsky et al. 2010]. This model most likely mimics CLL, in which NF-kB can also be constitutively activated [Dom ech et al. 2012]. Hence, BCL2 over-expression may improve other aberrant signaling pathways, thereby advertising survival and proliferation of CLL cells. BCL2 over-expression prevents apoptosis despite endogenous and exogenous death stimuli. Paradoxically, these cells are `primed for death', given that it would hypothetically take a minor change in BCL2 activity for apoptosis to be induced. In a preliminary study utilizing BH3-profiling, a functional assay which assesses the proximity of cells for the threshold of apoptosis, Davids and colleagues demonstrated that CLL cells fromperipheral blood are very primed. Though a tiny quantity of samples had been studied, it was suggested that improved priming is linked with improved clinical response [Davids et al. 2012]. This has been realized by the unexpected tumor lysis syndrome (TLS) after ABT-199 VE.14;18) in which the BCL2 gene at 18q21 is placed into juxtaposition with all the immunoglobulin heavy-chain locus title= fnhum.2017.00272 at 14q32. On the other hand, BCL2 expression is elevated in approximately 95 of individuals with CLL and to a level equivalent to t(14;18)-bearing cells in 70 . Larger levels are observed in CLL cells derived from lymph nodes, compared with bone marrow or peripheral blood [Hanada et al. 1993; Papakonstantinou et al. 2001]. Over-expression in CLL seems to be explained by epigenetic mechanisms, which includes hypomethylation of the BCL2 gene; super-enhancer activity as demonstrated by H3K27 acetylation chromatin analysis [Ott et al. 2015]; or post-transcriptional regulation by the absence of microRNA miR-15a and miR-16-1, positioned around the lengthy arm of chromosome 13, a region characteristically deleted in much more than 50 of CLL patients [Hern dez-S chez et al.