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Bhoi, Sujata
Publications (9 of 9) Show all publications
Papakonstantinou, N., Ntoufa, S., Tsagiopoulou, M., Moysiadis, T., Bhoi, S., Malousi, A., . . . Stamatopoulos, K. (2019). Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia. International Journal of Cancer, 144(11), 2695-2706
Open this publication in new window or tab >>Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 11, p. 2695-2706Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL.

Keywords
CLL, stereotypy, DNA methylation, gene expression, TP63
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-384059 (URN)10.1002/ijc.31999 (DOI)000467099500009 ()30447004 (PubMedID)
Funder
EU, Horizon 2020, 644906Swedish Cancer SocietyKnut and Alice Wallenberg FoundationEU, Horizon 2020, 692298Swedish Research CouncilEU, Horizon 2020, 702714
Note

De 3 första författarna delar förstaförfattarskapet.

Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Bhoi, S., Mansouri, L., Castellano, G., Sutton, L. A., Papakonstantinou, N., Queiros, A., . . . Rosenquist, R. (2017). DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?. Paper presented at 22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN. Haematologica, 102(Suppl. 2), 68-68, Article ID P244.
Open this publication in new window or tab >>DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?
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2017 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 68-68, article id P244Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2017
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377412 (URN)000404127001140 ()
Conference
22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
Bhoi, S. (2017). Prognostic markers and DNA methylation profiling in lymphoid malignancies. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Prognostic markers and DNA methylation profiling in lymphoid malignancies
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confirming its prognostic impact in multivariate analysis, we could identify 30% of IGHV-mutated CLL (M-CLL) cases with high expression and poor outcome, which otherwise lacked any other poor-prognostic marker. In paper II, we investigated the prognostic impact of a previously reported 5 CpG signature that divides CLL patients into three clinico-biological subgroups, namely naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL) and intermediate CLL (i-CLL), in 135 CLL patients using pyrosequencing. We validated the signature as an independent marker in multivariate analysis and further reported that subset #2 cases were predominantly classified as i-CLL, although displaying a similar outcome as n-CLL. In paper III, we investigated the methylation status and expression level of miR26A1 in both CLL (n=70) and MCL (n=65) cohorts. High miR26A1 methylation was associated with IGHV-unmutated (U-CLL) and shorter overall survival (OS) in CLL, while it was uniformly hypermethylated in MCL. Furthermore, overexpression of miR26A1 resulted in significant downregulation of EZH2 that in turn led to increased apoptosis. In paper IV, we performed DNA methylation profiling in 176 CLL cases assigned to one of 8 major stereotyped subsets (#1-8) in relation to non-subset CLL (n=325) and different normal B-cell subpopulations. Principal component analysis of subset vs. non-subset CLL revealed that U-CLL and M-CLL subsets generally clustered with n-CLL and m-CLL, respectively, indicating common cellular origins. In contrast, subset #2 emerged as the first defined member of the i-CLL subgroup, which in turn alludes to a distinct cellular origin for subset #2 and i-CLL patients. Altogether, this thesis confirms the prognostic significance of RNA and epigenetic-based markers in CLL, provides insight into the mechanism of miRNA deregulation in lymphoid malignancies and further unravels the DNA methylation landscape in stereotyped subsets of CLL.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1363
Keywords
Lymphoid malignancies, CLL, MCL, prognostic markers, micro-RNA, methylation, stereotyped subsets
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-328616 (URN)978-91-513-0053-5 (ISBN)
Public defence
2017-10-19, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-09-26 Created: 2017-08-28 Last updated: 2017-10-17
Kopparapu, P. K., Bhoi, S., Mansouri, L., Arabanian, L. S., Plevova, K., Pospisilova, S., . . . Kanduri, M. (2016). Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma: Impact on EZH2 expression. Epigenetics, 11(5), 335-343
Open this publication in new window or tab >>Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma: Impact on EZH2 expression
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2016 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 11, no 5, p. 335-343Article in journal (Refereed) Published
Abstract [en]

Downregulation of miR26A1 has been reported in various B-cell malignancies; however, the mechanism behind its deregulation remains largely unknown. We investigated miR26A1 methylation and expression levels in a well-characterized series of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). From 450K methylation arrays, we first observed miR26A1 (cg26054057) as uniformly hypermethylated in MCL (n = 24) (all >75%), while CLL (n = 18) showed differential methylation between prognostic subgroups. Extended analysis using pyrosequencing confirmed our findings and real-time quantitative PCR verified low miR26A1 expression in both CLL (n = 70) and MCL (n = 38) compared to normal B-cells. Notably, the level of miR26A1 methylation predicted outcome in CLL, with higher levels seen in poor-prognostic, IGHV-unmutated CLL. Since EZH2 was recently reported as a target for miR26A1, we analyzed the expression levels of both miR26A1 and EZH2 in primary CLL samples and observed an inverse correlation. By overexpression of miR26A1 in CLL and MCL cell lines, reduced EZH2 protein levels were observed using both Western blot and flow cytometry. In contrast, methyl-inhibitor treatment led to upregulated miR26A1 expression with a parallel decrease of EZH2 expression. Finally, increased levels of apoptosis were observed in miR26A1-overexpressing cell lines, further underscoring the functional relevance of miR26A1. In summary, we propose that epigenetic silencing of miR26A1 is required for the maintenance of increased levels of EZH2, which in turn translate into a worse outcome, as shown in CLL, highlighting miR26A1 as a tumor suppressor miRNA.

Keywords
Chronic lymphocytic leukemia, DNA methylation, mantle cell lymphoma, microRNA, tumor suppressor
National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-298924 (URN)10.1080/15592294.2016.1164375 (DOI)000377274700002 ()27052808 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2016-07-12 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
Bhoi, S., Baliakas, P., Cortese, D., Mattsson, M., Sevov, M., Smedby, K. E., . . . Mansouri, L. (2016). UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia? [Letter to the editor]. Haematologica, 101(2), E63-E65
Open this publication in new window or tab >>UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, p. E63-E65Article in journal, Letter (Refereed) Published
Keywords
CLL; UGT2B17; prognostic markers
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-271300 (URN)10.3324/haematol.2015.136440 (DOI)000379156300007 ()26589911 (PubMedID)
Available from: 2016-01-07 Created: 2016-01-07 Last updated: 2019-04-01
Mansouri, L., Sutton, L.-A., Ljungström, V., Bondza, S., Arngården, L., Bhoi, S., . . . Rosenquist Brandell, R. (2015). Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia. Journal of Experimental Medicine, 212(6), 833-843
Open this publication in new window or tab >>Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia
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2015 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed) Published
Abstract [en]

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-279237 (URN)10.1084/jem.20142009 (DOI)000355569300001 ()25987724 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), b2011080Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), CA81554; CA081554EU, European Research Council, 259796EU, FP7, Seventh Framework Programme, 306242
Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-01-10Bibliographically approved
Tugues, S., Roche, F., Noguer, O., Orlova, A., Bhoi, S., Padhan, N., . . . Claesson-Welsh, L. (2014). Histidine-Rich Glycoprotein Uptake and Turnover Is Mediated by Mononuclear Phagocytes.. PLoS ONE, 9(9), e107483
Open this publication in new window or tab >>Histidine-Rich Glycoprotein Uptake and Turnover Is Mediated by Mononuclear Phagocytes.
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e107483-Article in journal (Refereed) Published
Abstract [en]

Histidine-rich glycoprotein (HRG) is implicated in tumor growth and metastasis by regulation of angiogenesis and inflammation. HRG is produced by hepatocytes and carried to tissues via the circulation. We hypothesized that HRG's tissue distribution and turnover may be mediated by inflammatory cells. Biodistribution parameters were analyzed by injection of radiolabeled, bioactive HRG in the circulation of healthy and tumor-bearing mice. 125I-HRG was cleared rapidly from the blood and taken up in tissues of healthy and tumor-bearing mice, followed by degradation, to an increased extent in the tumor-bearing mice. Steady state levels of HRG in the circulation were unaffected by the tumor disease both in murine tumor models and in colorectal cancer (CRC) patients. Importantly, stromal pools of HRG, detected in human CRC microarrays, were associated with inflammatory cells. In agreement, microautoradiography identified 125I-HRG in blood vessels and on CD45-positive leukocytes in mouse tissues. Moreover, radiolabeled HRG bound in a specific, heparan sulfate-independent manner, to differentiated human monocytic U937 cells in vitro. Suppression of monocyte differentiation by systemic treatment of mice with anti-colony stimulating factor-1 neutralizing antibodies led to reduced blood clearance of radiolabeled HRG and to accumulation of endogenous HRG in the blood. Combined, our data show that mononuclear phagocytes have specific binding sites for HRG and that these cells are essential for uptake of HRG from blood and distribution of HRG in tissues. Thereby, we confirm and extend our previous report that inflammatory cells mediate the effect of HRG on tumor growth and metastatic spread.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-232935 (URN)10.1371/journal.pone.0107483 (DOI)000343679800035 ()25243896 (PubMedID)
Available from: 2014-09-27 Created: 2014-09-27 Last updated: 2018-01-11Bibliographically approved
Mansouri, L., Sutton, L.-A., Ljungström, V., Bondza, S., Arngården, L., Bhoi, S., . . . Rosenquist, R. (2014). Recurrent Mutations within the Nfkbie gene: A Novel Mechanism for NF-kappa B Deregulation in Aggressive Chronic Lymphocytic Leukemia. Blood, 124(21)
Open this publication in new window or tab >>Recurrent Mutations within the Nfkbie gene: A Novel Mechanism for NF-kappa B Deregulation in Aggressive Chronic Lymphocytic Leukemia
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2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-249073 (URN)000349242707052 ()
Available from: 2015-04-17 Created: 2015-04-10 Last updated: 2017-12-04Bibliographically approved
Rosenquist Brandell, R., Cortese, D., Bhoi, S., Mansouri, L. & Gunnarsson, R. (2013). Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand?. Leukemia and Lymphoma, 54(11), 2351-2364
Open this publication in new window or tab >>Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand?
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2013 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 11, p. 2351-2364Article, review/survey (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease where the majority of patients have an indolent disease course, while others may experience a far more aggressive disease, treatment failure and poor overall survival. During the last two decades, there has been an intense search to find novel biomarkers that can predict prognosis as well as guide treatment decisions. Two of the most reliable molecular prognostic markers, both of which are offered in routine diagnostics, are the immunoglobulin heavy chain variable (IGHV) gene mutational status and fluorescence in situ hybridization (FISH) detection of prognostically relevant genomic aberrations (e.g. 11q-, 13q-, +12 and 17p-). In addition to these markers, a myriad of additional biomarkers have been postulated as potential prognosticators in CLL, on the protein (e.g. CD38, ZAP70, TCL1), the RNA (e.g. LPL, CLLU1, micro-RNAs) and the genomic (e.g. TP53, NOTCH1, SF3B1 and BIRC3 mutations) level. Efforts are now being made to test these novel markers in larger patient cohorts as well as in prospective trials, with the ultimate goal to combine the "best" markers in a "CLL prognostic index" applicable for the individual patient. Although it is clear that these studies have significantly improved our knowledge regarding both prognostication and the biology of the disease, there is still an immediate need for recognizing biomarkers that can predict therapy response, and efforts should now focus on addressing this pertinent issue. In the present article, we review the extensive literature in the field of prognostic markers in CLL, focus on the most clinically relevant markers and discuss future directions regarding biomarkers in CLL.

Keywords
Chronic lymphocytic leukemia, prognostic markers, predictive markers, genetic aberrations, gene mutations, RNA-based markers, prognostic index
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210930 (URN)10.3109/10428194.2013.783913 (DOI)000325498900008 ()
Available from: 2013-11-18 Created: 2013-11-18 Last updated: 2017-12-06Bibliographically approved
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