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Unique cyclic nucleotide signaling i...

Meyers, John Alexander.

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Unique cyclic nucleotide signaling in chronic lymphocytic leukemia represents a potential novel therapeutic target.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Unique cyclic nucleotide signaling in chronic lymphocytic leukemia represents a potential novel therapeutic target./
作者:	Meyers, John Alexander.
面頁冊數:	144 p.
附註:	Source: Dissertation Abstracts International, Volume: 71-03, Section: B, page: 1611.
Contained By:	Dissertation Abstracts International71-03B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3399547
ISBN:	9781109653441

Unique cyclic nucleotide signaling in chronic lymphocytic leukemia represents a potential novel therapeutic target.
Meyers, John Alexander.

Unique cyclic nucleotide signaling in chronic lymphocytic leukemia represents a potential novel therapeutic target. - 144 p.

Source: Dissertation Abstracts International, Volume: 71-03, Section: B, page: 1611.

Thesis (Ph.D.)--Boston University, 2010.

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the Western world yet no curative treatment exists. Previous work has established that inhibition of phosphodiesterase-4 (PDE4) is sufficient to selectively induce apoptosis in CLL cells by increasing the concentration of the second messenger cyclic AMP (cAMP). We sought to establish the extent and mechanism of CLL's selective sensitivity to PDE4 inhibitors and to determine their efficacy in combination with glucocorticoids. Primary CLL cells were treated with rolipram, a prototypical PDE4 inhibitor, and compared with comparably treated normal B and T cells obtained from healthy donors. In both CLL and normal B cells intracellular cAMP levels rose rapidly upon rolipram exposure, whereas T cells showed little to no such increase. Likewise, rolipram induced phosphorylation of the cAMP downstream transcription factor targets CREB/ATF1 in nearly all CLL and B cells while normal T cells demonstrated a far less robust response. In contrast, CREB/ATF1 phosphorylation occurred in normal T cells when rolipram was combined with a PDE3 inhibitor.

ISBN: 9781109653441Subjects--Topical Terms:

1017719
Biology, Molecular.

Unique cyclic nucleotide signaling in chronic lymphocytic leukemia represents a potential novel therapeutic target.
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245 1 0 $a Unique cyclic nucleotide signaling in chronic lymphocytic leukemia represents a potential novel therapeutic target.
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500 $a Source: Dissertation Abstracts International, Volume: 71-03, Section: B, page: 1611.
500 $a Adviser: Adam Lerner.
502 $a Thesis (Ph.D.)--Boston University, 2010.
520 $a Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the Western world yet no curative treatment exists. Previous work has established that inhibition of phosphodiesterase-4 (PDE4) is sufficient to selectively induce apoptosis in CLL cells by increasing the concentration of the second messenger cyclic AMP (cAMP). We sought to establish the extent and mechanism of CLL's selective sensitivity to PDE4 inhibitors and to determine their efficacy in combination with glucocorticoids. Primary CLL cells were treated with rolipram, a prototypical PDE4 inhibitor, and compared with comparably treated normal B and T cells obtained from healthy donors. In both CLL and normal B cells intracellular cAMP levels rose rapidly upon rolipram exposure, whereas T cells showed little to no such increase. Likewise, rolipram induced phosphorylation of the cAMP downstream transcription factor targets CREB/ATF1 in nearly all CLL and B cells while normal T cells demonstrated a far less robust response. In contrast, CREB/ATF1 phosphorylation occurred in normal T cells when rolipram was combined with a PDE3 inhibitor.
520 $a Concordantly, normal T cells were found to contain higher levels of PDE3B protein and transcript than CLL or normal B cells. Among the three cell types, only CLL cells underwent rolipram-induced apoptosis. Furthermore, the global transcriptional effect of rolipram was greatest in CLL cells, and was characterized by groups of tightly coregulated genes with very low or very high basal levels. Both rolipram-induced transcriptional changes and CREB/ATF1 phosphorylation were partially blocked by co-treatment with a protein kinase A inhibitor. In rolipram-treated CLL cells, glucocorticoid receptor (GR) protein and transcript levels were robustly increased and the latter was predominately composed of a splice isoform driven by the GR 1A3 promoter. Rolipram augmented dexamethasone-induced apoptosis in many patient CLL samples. This apoptotic effect was apparently irreversible, occurred despite rolipram withdrawal and over the same short period required for GR transcript upregulation. Taken together the data suggest that constitutive PDE4 activity is necessary for CLL cell survival and that PDE4 inhibitors may be exploited for therapeutic benefit in CLL.
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