Nuclear chromatin patterns in 3 glucocorticoid-resistant RPMI 8226 human myeloma cell sub-lines: Correlations with cell growth and immunological phenotype

Genty, V.; El-Khoury, Victoria; Liautaud-Roger, F; Dine, G.; Dufer, Jean

doi:10.4161/cbt.4.8.1890

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…However, the recognition of prognostically relevant cell atypias and maturation of the neoplastic plasma cells is dependent on the morphologist's expertise, thus leading to a considerable inter-observer variability. On the other hand, experimental studies using computerized image analysis have shown that subvisible modifications of the chromatin architecture in myeloma cells are associated with important changes of cell physiology, such as acquired drug resistance [7]. The quantitative analysis of the distribution pattern of chromatin and other nuclear components has been shown to be of prognostic importance in several neoplasias [8]–[15].…”

Section: Introductionmentioning

confidence: 99%

Fractal Characteristics of May-Grünwald-Giemsa Stained Chromatin Are Independent Prognostic Factors for Survival in Multiple Myeloma

et al. 2011

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BackgroundThe use of computerized image analysis for the study of nuclear texture features has provided important prognostic information for several neoplasias. Recently fractal characteristics of the chromatin structure in routinely stained smears have shown to be independent prognostic factors in acute leukemia. In the present study we investigated the influence of the fractal dimension (FD) of chromatin on survival of patients with multiple myeloma.MethodologyWe analyzed 67 newly diagnosed patients from our Institution treated in the Brazilian Multiple Myeloma Study Group. Diagnostic work-up consisted of peripheral blood counts, bone marrow cytology, bone radiograms, serum biochemistry and cytogenetics. The International Staging System (ISS) was used. In every patient, at least 40 digital nuclear images from diagnostic May-Grünwald-Giemsa stained bone marrow smears were acquired and transformed into pseudo-3D images. FD was determined by the Minkowski-Bouligand method extended to three dimensions. Goodness-of-fit of FD was estimated by the R2 values in the log-log plots. The influence of diagnostic features on overall survival was analyzed in Cox regressions. Patients that underwent autologous bone marrow transplantation were censored at the day of transplantation.Principal FindingsMedian age was 56 years. According to ISS, 14% of the patients were stage I, 39% were stage II and 47% were stage III. Additional features of a bad prognosis were observed in 46% of the cases. When stratifying for ISS, both FD and its goodness-of-fit were significant prognostic factors in univariate analyses. Patients with higher FD values or lower goodness-of-fit showed a worse outcome. In the multivariate Cox-regression, FD, R2, and ISS stage entered the final model, which showed to be stable in a bootstrap resampling study.ConclusionsFractal characteristics of the chromatin texture in routine cytological preparations revealed relevant prognostic information in patients with multiple myeloma.

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Section: Introductionmentioning

confidence: 99%

Fractal Characteristics of May-Grünwald-Giemsa Stained Chromatin Are Independent Prognostic Factors for Survival in Multiple Myeloma

et al. 2011

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“…For instance, LM displays significant increases in invasive bladder tumours as compared to superficial tumours (25) and appears linked (together with E and GLD) to tumour size in breast carcinomas (unpublished data). Moreover, we reported previously similar chromatin changes in 8226 cells resistant to glucocorticoids, suggesting that the observed alterations could represent a drug (and mechanism)-independent marker of drug-resistance in these myeloma cells (26). However, these chromatin changes in drug-resistant cells can be modulated by thalidomide treatment.…”

Section: Discussionmentioning

confidence: 85%

Thalidomide alters nuclear architecture without ABCB1 gene modulation in drug-resistant myeloma cells

Trussardi-Regnier¹

2009

Int J Oncol

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Abstract. ABCB1 gene overexpression has been described as an important mechanism for resistance to conventional chemotherapy in multiple myelomas. In the refractory multiple myelomas, other drug regimens have been successfully applied, including thalidomide treatments. Besides its well-documented anti-angiogenic effects, thalidomide therapy could result in a decrease in ABCB1 gene expression. In this study, we analysed the effects of a 24-h short-term treatment by thalidomide or its active metabolite phthaloyl glutamic acid (PGA) on nuclear chromatin higher-order organisation and ABCB1 gene expression in drug-sensitive and drug-resistant 8226 human myeloma cells. As compared to sensitive cells, 8226-Dox40 drug-resistant cells exhibited an increase in chromatin texture condensation and ABCB1 gene overexpression. At this gene promoter level, the -50 and -100 GC boxes displayed an unmethylated profile in drug-sensitive cells whereas drug-resistant cell promoter GC boxes were fully methylated. Thalidomide and PGA induced significant chromatin textural changes in 8226-Dox40 drug-resistant cells only with neither alteration in ABCB1 gene expression nor methylation profile of its promoter. Conversely thalidomide and PGA induced down-regulation of VEGF gene expression in both drug-sensitive and -resistant myeloma cells. These data suggest that short-term treatments by thalidomide or PGA do not induce any significant change on ABCB1 gene expression though they modulate chromatin supra-organisation in drug-resistant 8226 human myeloma cells.

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“…Cell culture. The RPMI-8226 human multiple myeloma cell (8226wt) and its glucocorticoid-resistant variants 8226d and 8226m selected upon long-term treatment with dexamethasone and methylprednisolone respectively, were kindly provided by Pr J. Dufer (Reims, France) and cultured as previously described (33,34). All experiments were performed with cells in exponential growth phase.…”

Section: Methodsmentioning

confidence: 99%

Histone deacetylases meet microRNA-associated MMP-9 expression regulation in glucocorticoid-sensitive and -resistant cell lines

Hentati-Kallel

Jan

Bernard

et al. 2016

International Journal of Oncology

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Glucocorticoids are largely used in the treatment of inflammatory pathologies and/or hematological malignancies and regulate the expression of a variety of genes involved in inflammation or metastasis such as matrix metalloproteinases (MMP). Long-term exposure to glucocorticoids can result in failure of responsiveness, which is often associated with an unwanted gene expression. Epigenetic mechanisms are involved in gene expression modulated after development of glucocorticoid resistance but how these mechanisms take place must be further studied. The effects of HDAC inhibitors (HDACi) in a context of glucocorticoid resistance are still not well understood and need to be further investigated. We hypothesized that acquired glucocorticoid resistance associated to HDACi could disturbs epigenetic landscape, especially miR expression, leading to a modulation of MMP-9 gene expression and/or protein secretion, described as largely involved in bone remodeling and tumor invasion in multiple myeloma. To this aim, we used sensitive RPMI-8226 cell line and its dexamethasone- and methylprednisolone-resistant derivatives. The resistant cell lines displayed an 'open chromatin' and an MMP-9 overexpression comparatively to the sensitive cell line. HDACi treatment with MS-275 increased even more MMP-9 overexpression not only at an mRNA level but also at the protein level. We showed that MMP-9 expression regulation was not directly linked with HAT/HDAC balance alterations but rather with the deregulation of MMP-9-targeting miRs. Then, we first demonstrated that miR‑149 downregulation was directly involved in the MMP-9 overexpression following a chronic glucocorticoid exposure and that MS-275 could amplify this overexpression by inhibition of miR‑149 expression and miR‑520c overexpression. Taken together, these results indicate that the use of HDACi in a context of acquired glucocorticoid resistance could modify the epigenetic landscape, highlighting the importance of taking the glucocorticoid response status into consideration in treatment with HDACi.

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Nuclear chromatin patterns in 3 glucocorticoid-resistant RPMI 8226 human myeloma cell sub-lines: Correlations with cell growth and immunological phenotype

Cited by 7 publications

References 37 publications

Fractal Characteristics of May-Grünwald-Giemsa Stained Chromatin Are Independent Prognostic Factors for Survival in Multiple Myeloma

Fractal Characteristics of May-Grünwald-Giemsa Stained Chromatin Are Independent Prognostic Factors for Survival in Multiple Myeloma

Thalidomide alters nuclear architecture without ABCB1 gene modulation in drug-resistant myeloma cells

Histone deacetylases meet microRNA-associated MMP-9 expression regulation in glucocorticoid-sensitive and -resistant cell lines

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