IL-4 and interferon gamma regulate expression of inducible nitric oxide synthase in chronic lymphocytic leukemia cells

Levesque, Marc C.; Misukonis, Mary A.; O'Loughlin, CW; Chen, Y; Beasley, Bethany E.; Wilson, Denney L.; Adams, DJ; Silber, Robert; Weinberg, J. Brice

doi:10.1038/sj.leu.2402783

Cited by 37 publications

(28 citation statements)

References 70 publications

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“…In agreement with Zhao et al 21 and Levesque et al, 34 B lymphocytes from 90% of B-CLL patients constitutively expressed iNOS transcripts as assessed by RT-PCR of exon 26 in contrast to a 43% positivity observed for healthy donors. Different from normal B cells, these results suggest that there is an in vivo basal transcription for the iNOS gene, in the case of B-CLL cells.…”

Section: Discussionsupporting

confidence: 75%

“…26 Zhao et al 21 reported the spontaneous expression of iNOS mRNA by two pairs of primers, one of them amplifying exon 26 and the other exons 8-11, whereas Levesque et al 34 found similar results for primers amplifying exons 9-10. These results indicate that in B-CLL cells, splicing variants involving either exons 8-9 or 9-11 have never been detected.…”

Section: Discussionmentioning

confidence: 75%

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Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions

et al. 2003

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Functional inducible NOS (iNOS) may be involved in the prolonged lifespan of chronic lymphocytic leukemia cells (B-CLL), although the exact mechanisms implicated remain elusive as yet. In this work, we have examined iNOS expression in normal B lymphocytes and B-CLL cells in pro-and antiapoptotic conditions. Our results demonstrate: (1) The existence of a new splice variant characterized by a complete deletion of exon 14 (iNOS 13-16 14del ), which was preferentially detected in normal B lymphocytes and may represent an isoform that could play a role in the regulation of enzyme activity. (2) The existence of another alternatively spliced iNOS mRNA transcript involving a partial deletion of the flavodoxin region (iNOS 13-16 neg ) was correlated to a decreased B-CLL cell viability. The 9-b-D-arabinofuranosyl-2-fluoradenine or fludarabine (F-ara) treatment induced iNOS 13-16 neg transcript variants, whereas IL-4 enhanced both the transcription of variants, including these exons (iNOS 13-16 pos ), and the expression of a 122 kDa iNOS protein. These results suggest that in B-CLL, a regulation process involving nitric oxide ( K NO) levels could occur by a post-transcriptional mechanism mediated by soluble factors. Our results also provide an insight into a new complementary proapoptotic action of F-ara in B-CLL by the induction of particular iNOS splice variants, leading to the activation of a caspase-3-dependent apoptotic pathway.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 75%

Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions

et al. 2003

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“…6 Furthermore, we also showed the constitutive expression of a functional NO synthase (NOS) of the inducible type (iNOS) in B-CLL cells, which was absent in normal B lymphocytes, 7 a result confirmed by a study also showing that IFN-g and IL-4 stimulated iNOS expression in the leukemic cells. 8 In our study, the inhibition of endogenous NO release by ex vivo treatment of the leukemic cells with NOS inhibitors was found to result in the induction of apoptosis, indicating that the NO pathway may contribute to prevent programmed cell death in B-CLL. 7 Thus, drugs aimed at downregulating iNOS expression or activity could be of potential therapeutic interest for this leukemia.…”

Section: Introductionmentioning

confidence: 91%

Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia

et al. 2003

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Flavopiridol, an inhibitor of cyclin-dependent kinases and other protein kinases, induces in vitro apoptosis of malignant cells from B-cell chronic lymphocytic leukemia (B-CLL). Previously, we reported that nitric oxide (NO), produced by an inducible NO synthase (iNOS), spontaneously expressed by the B-CLL cells, contributed to their deficiency in apoptosis. In the present work, we show that ex vivo treatment of leukemic cells from B-CLL patients with flavopiridol results in the inhibition of iNOS expression, as determined by immunofluorescence and Western blotting, and in a marked inhibition of NO production measured in situ with a specific fluorescent probe (DAF-2 DA). These effects are accompanied by membrane, mitochondrial and nuclear events of apoptosis. Flavopiridol exposure also results in the stimulation of caspase 3 activity and in caspasedependent cleavage of p27 kip1 , a negative regulator of the cell cycle, which is overexpressed in B-CLL. Thus, flavopiridol is capable of downregulating both iNOS and p27 kip1 expression in B-CLL cells. Furthermore, flavopiridol-promoted apoptosis is partly reverted by an NO donor, suggesting that inhibition of the NO pathway could participate in the apoptotic effects of flavopiridol on the leukemic cells.

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“…13 In addition, 23 Furthermore, HF also downregulates two other proteins, iNOS and p27 kip1 , which are overexpressed in B-CLL cells. 17,25 The former, iNOS, is responsible for the production of NO that displays antiapoptotic properties in B-CLL cells 17,24 and is a component of their resistance to cell death. 28 We showed recently that several plant-derived compounds, such as flavopiridol, 21 polyphenols (including resveratrol) and their acetate derivatives as well as a synthetic aminoflavone, induced both apoptosis of B-CLL patients' cells and downregulation of iNOS expression and NO production.…”

Section: Discussionmentioning

confidence: 99%

“…17,24 Western blot experiments showed clearly that treatment of B-CLL cells with HF induced a dose-dependent reduction of iNOS expression and that this downregulation correlated with PARP-1 cleavage, taken as a marker of caspase-dependent apoptosis (Figure 3a). Note also that the inhibition of iNOS expression seen with 5 mg/ ml HF was almost as strong as the effect of 1 mM flavopiridol ( Figure 3c) which was reported recently.…”

Section: Hf Inhibits Inos Expression and No Production In B-cll Cellsmentioning

confidence: 99%

Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia

Quiney

Billard

et al. 2006

Leukemia

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The effects of the hyperforin (HF), a natural phloroglucinol purified from Hypericum perforatum, were investigated ex vivo on leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL). HF was found to promote apoptosis of B-CLL cells, as shown by time-and dose-dependent stimulation of phosphatidylserine externalization and DNA fragmentation, by disruption of the mitochondrial transmembrane potential, caspase-3 activation and cleavage of the caspase substrate PARP-1. Moreover, HF-induced downregulation of Bcl-2 and Mcl-1, two antiapoptotic proteins that control mitochondrial permeability. HF also downregulated two proteins which are overexpressed by B-CLL patients' cells, the cell cycle inhibitor p27 kip1 through caspase-dependent cleavage into a p23 form, and the nitric oxid (NO) synthase of type 2 (inducible NO synthase). This latter was accompanied by reduction in the production of NO known to be antiapoptotic in B-CLL cells. Preventing effects of the general caspase inhibitor z-VAD-fmk indicated that HF-promoted apoptosis of B-CLL cells was mostly caspase dependent. Furthermore, normal B lymphocytes purified from healthy donors appeared less sensitive to HF-induced apoptosis than B-CLL cells. These results indicate that HF may be of interest in the development of new therapies for B-CLL based on the induction of apoptosis and combination with cell cycle-dependent antitumor drugs.

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IL-4 and interferon gamma regulate expression of inducible nitric oxide synthase in chronic lymphocytic leukemia cells

Cited by 37 publications

References 70 publications

Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions

Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions

Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia

Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia

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