Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

Giné, Eva; Crespo, Marta; Muntañola, Ana; Calpe, Eva; Baptista, Maria Joao; Villamor, Neus; Montserrat, Emili; Bosch, Francesc

doi:10.3324/haematol.11546

Cited by 21 publications

(21 citation statements)

References 33 publications

(41 reference statements)

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“…Acid or high ionic buffers added to the nuclei disrupt the histone-DNA interactions solubilizing the proteins. While nuclei isolation allows for the analysis of chromatin bound histones, there is increasing evidence that extra-chromatin histones have functional roles [28,29,33-36]. Konishi et al demonstrated that histones could be isolated from cellular compartments and subsequently characterized by LC-MS [29].…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the function of histone H1 on chromatin structure, the histone H1.2 isoform has been shown to have extra-chromatin function [28-30]. Confocal imaging of mitotic fibroblasts have shown histone H1.2 localized to the cytosol demonstrating compartmental mobility in vitro [30].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, several groups have illustrated histone H1.2 is released to the cytoplasm following X-ray induced double strand breaks prompting a Bak dependent release of cytochrome C from the mitochondria and activation of caspase-3, caspase-7 [29,31,32]. Giné et al reported translocation of histone H1.2 to the cytoplasm in response to therapeutic treatment in chronic lymphocytic leukemia primary cells (CLL) [28]. Although cytoplasmic function of histone H1.2 has been established, the molecular signaling, transport chaperones and cofactors of this process are still to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Isolation and analysis of linker histones across cellular compartments

Harshman

Chen

Branson

et al. 2013

Journal of Proteomics

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Analysis of histones, especially histone H1, is severely limited by immunological reagent availability. This paper describes the application of cellular fractionation with LC-MS for profiling histones in the cytosol and upon chromatin. First, we show that linker histones enriched by cellular fractionation gives less nuclear contamination and higher histone content than when prepared by nuclei isolation. Second, we profiled the soluble linker histones throughout the cell cycle revealing phosphorylation increases as cells reach mitosis. Finally, we monitored histone H1.2–H1.5 translocation to the cytosol in response to the CDK inhibitor flavopiridol in primary CLL cells treated ex vivo. Data shows all H1 variants translocate in response to drug treatment with no specific order to their cytosolic appearance. The results illustrate the utility of cellular fractionation in conjunction with LC-MS for the analysis of histone H1 throughout the cell.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Isolation and analysis of linker histones across cellular compartments

Harshman

Chen

Branson

et al. 2013

Journal of Proteomics

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“…Moreover, following UV-induced damage, the histone isoform, H1.2, translocates from the nucleus to the cytoplasm and triggers apoptosis 10 . Thus, one source of extracellular histones including histone H1 10, 31 might be those re-localised to the cytoplasm while another could be those released from disintegrating nuclei. Potentially, extracellular histones could act both at the cell surface and within the cytoplasm following uptake.…”

Section: Discussionmentioning

confidence: 99%

Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia

et al. 2013

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In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.

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“…67 A novel apoptogenic mechanism, cytosolic Histone H1.2 release, was also shown to be p53 dependent. 68 The predictive value of trisomy 12 is abrogated when fludarabine-containing regimens are used (S. Stilgenbauer, personal communication). Patients with deletions in 17p or 11q have been shown to respond to flavopiridol.…”

Section: Cytogenetics/fishmentioning

confidence: 99%

Impact of cytogenetic and molecular prognostic markers on the clinical management of chronic lymphocytic leukemia

Hauswirth¹,

Jäger²

2008

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nsubgroups for further analysis in microarray studies. Gene expression profiling revealed the association of a number of genes previously thought to be unrelated to CLL. Depending on the use of CD19-selected/T-cell depleted or unpurified B-CLL samples, a variety of markers have been found since the initial experiments of Klein and Rosenwald in 2001. 19,52-54 A comprehensive analysis of more than 500 patients suggests a complex expression pattern with many CLL subgroups and overlaps.55 Furthermore, Fernàndez et al. have shown considerable intra-individual modulation of gene expression patterns during the course of disease. 56The first established marker emerging from microarray analysis was the receptor kinase ZAP-70. The prognostic value of this genetic marker has now been well established by FACS-analysis or PCR.33,34,57-62 ZAP-70 protein expression predicts for treatment-free survival (TFS) and overall survival independently of mutation status. While convincing results were obtained by several groups using different protein detection methods, efforts by the European Initiative in CLL Research (ERIC) to standardize their study approach have proved problematic.63 Furthermore, investigations into the association with IgVH mutational status have yielded differing results, particularly 17p-samples cluster in the ZAP-70 negative group.64 Assessment of ZAP-70 mRNA expression by real time PCR requires positive (CD19) or negative selection of B-cells. 33,34 Despite these drawbacks, ZAP-70 is a useful clinical marker and may also serve as a future target for specific signal transduction inhibitors.Among the markers with an even stronger correlation to IgVH mutational status, 52,53 lipoprotein lipase has been extensively studied. [35][36][37][38][39][40] Its association with other markers (cytogenetic risk groups, molecular markers) as well as patient outcome (time to treatment, overall survival) is also strong. Lipoprotein lipase is a stable marker which has been studied by real-time PCR in several large series using purified or unpurified CLL cells or even whole blood. No difference between purified and unpurified samples was observed in several studies, indicating its potential for easy and general use. Its specificity regarding IgVH mutational status is 89%, with a sensitivity of 68%, a positive predictive value of 83% and a negative predictive value of 78%.39 Discordant results are also observed.36 Lipoprotein lipase can be combined with a downregulated marker (ADAM29) to increase specificity.35 While lipoprotein lipase protein can also be detected on normal B-cells, its cytoplasmatic expression correlates well with RNA levels. 36 We have used the level of lipoprotein lipase-expression as a discriminator for microarray analysis.19 Several markers emerging from this experiment have been validated by real time PCR. Among those, septin 10 and dystrophin (DMD) were strongly associated with time to treatment. The prognostic significance of some of these factors have also be...

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Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

Abstract: BackgroundThe aim of this study was to analyze whether in chronic lymphocytic leukemia the cytosolic release of histone H1.2, a new apoptogenic mechanism induced by DNA damage, was associated with the presence of genetic abnormalities and with the response to treatment.

Cited by 21 publications

References 33 publications

Isolation and analysis of linker histones across cellular compartments

Isolation and analysis of linker histones across cellular compartments

Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia

Impact of cytogenetic and molecular prognostic markers on the clinical management of chronic lymphocytic leukemia

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