Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

López-Corral, Lucía; Corchete, Luis A.; Sarasquete, María Eugenia; Mateos, María Victoria; García‐Sanz, Ramón; Fermiñán, Encarnación; Lahuerta, Juan José; Bladé, Joan; Oriol, Albert; Teruel, Ana Isabel; Martino, M.L.; Hernández, José; Hernández-Rivas, Jesús María; Burguillo, F.J.; Miguel, Jesús F. San; Gutiérrez, Norma C.

doi:10.3324/haematol.2013.087809

Cited by 70 publications

(70 citation statements)

References 57 publications

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“…Afterward, RNA was amplified, labeled, and subsequently hybridized to the Human Gene 1.0 ST Array (Affymetrix). 31 Normalization was carried out by using the expression console (Affymetrix) with the Robust Multi-array Average algorithm, which includes background correction, normalization, and calculation of expression values (log2). 22 The SIMFIT (http://www.simfit.org.uk/) statistical software was used to perform hierarchical clustering analyses based on Euclidean distance as distances and the group average linkage method.…”

Section: Cd22mentioning

confidence: 99%

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The cellular origin and malignant transformation of Waldenström macroglobulinemia

Paiva

Corchete

Vidriales

et al. 2015

Blood

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Key Points• Benign (ie, IgM MGUS and smoldering WM) clonal B cells already harbor the phenotypic and molecular signatures of the malignant WM clone.• Multistep transformation from benign (ie, IgM MGUS and smoldering WM) to malignant WM may require specific copy number abnormalities.Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n 5 22), smoldering (n 5 16), and symptomatic WM (n 5 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25 2 CD22 1 B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25 1 CD221low ) B-cell counterpart. The frequency of specific copy number abnormalities [14, del(6q23.3-6q25.3), 112, and 118q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P 5 .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone. (Blood. 2015;125(15):2370-2380

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Section: Cd22mentioning

confidence: 99%

“…22,31 To identify the most relevant biological mechanisms, pathways, and functional categories involved according to differently expressed genes, the ingenuity pathway analysis (Ingenuity Systems, www.ingenuity.com) was used. Full microarray data are available at the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/; accession number GSE61597).…”

mentioning

confidence: 99%

The cellular origin and malignant transformation of Waldenström macroglobulinemia

Paiva

Corchete

Vidriales

et al. 2015

Blood

View full text Add to dashboard Cite

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“…A DNA microarray dataset generated from healthy donors and MM patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and MM, 16 …”

Section: Geo Dataset Analysesmentioning

confidence: 99%

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

Zhang

Tong

Tang

et al. 2016

Blood

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Key Points• HERC4 is the first identified ubiquitin ligase that mediates c-Maf ubiquitination and degradation.• HERC4 suppresses MM cell proliferation and delays MM tumor growth.The transcription factor c-Maf is extensively involved in the pathophysiology of multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, affinity chromatography and mass spectrometry were used to identify c-Maf ubiquitination-associated proteins, from which the E3 ligase HERC4 was found to interact with c-Maf and catalyzed its polyubiquitination and subsequent proteasome-mediated degradation. HERC4 mediated polyubiquitination at K85 and K297 in c-Maf, and this polyubiquitination could be prevented by the isopeptidase USP5. Further analysis on the NCI-60 cell line collection revealed that RPMI 8226, a MM-derived cell line, expressed the lowest level of HERC4. Primary bone marrow analysis revealed HERC4 expression was high in normal bone marrow, but was steadily decreased during myelomagenesis. These findings suggested HERC4 played an important role in MM progression. Moreover, ectopic HERC4 expression decreased MM proliferation in vitro, and delayed xenograft tumor growth in vivo. Therefore, modulation of c-Maf ubiquitination by targeting HERC4 may represent a new therapeutic modality for MM. (Blood. 2016;127(13):1676-1686

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“…Nevertheless, the expression status of CRISP3 and its potential as a peripheral blood biomarker in human MM remains to be determined. Data of human peripheral blood samples from the GEO repository may be merged together to produce a large sample data, and this super array data possesses a distinguished expression pattern, as observed in previous studies that used tissue samples (31,32). The present study identified that the gene expression of MM peripheral blood also possessed a marked pattern, even in the merged data.…”

Section: Discussionmentioning

confidence: 55%

Inï¿½silico analysis identifies CRISP3 as a potential peripheral blood biomarker for multiple myeloma: From data modeling to validation with RT-PCR

et al. 2018

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Abstract. Octamer-binding protein 2 (Oct2) binds to the ATGCAAAT octamer on the IgH enhancer and stimulates IgH expression in human multiple myeloma (MM). Cysteine-rich secreted protein 3 (CRISP3) possesses the ATGCAAAT sequence and thus is activated by Oct2 in mouse B cells, suggesting that CRISP3 may be activated in and be a potential biomarker for MM. The present study involved a meta-analysis of the gene expression profiling data of human MM peripheral blood. Significantly expressed genes were analyzed on merged super array microarray data and selected sample data with significantly expressed genes were additionally analyzed by principal component analysis and Bayesian probit regression. CRISP3, Oct2, Apha-1B-glycoprotein (A1GB) and Cyclin D2 (CCND2) were validated in clinical MM peripheral blood samples using reverse transcription quantitative polymerase chain reaction. In the gene expression profiling data, CRISP3 was significantly upregulated and had certain proportions on the discriminated principal component of significantly expressed gene sample data. RT-qPCR analysis revealed CRISP3 was significantly upregulated in MM. Therefore, CRISP3 is a potential peripheral blood biomarker for MM.

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Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

Cited by 70 publications

References 57 publications

The cellular origin and malignant transformation of Waldenström macroglobulinemia

The cellular origin and malignant transformation of Waldenström macroglobulinemia

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

Inï¿½silico analysis identifies CRISP3 as a potential peripheral blood biomarker for multiple myeloma: From data modeling to validation with RT-PCR

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