Genome‐wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles

Mosca, Laura; Musto, Pellegrino; Todoerti, Katia; Barbieri, Marzia; Agnelli, Luca; Fabris, Sonia; Tuana, Giacomo; Lionetti, Marta; Bonaparte, Eleonora; Sirchia, Silvia Maria; Grieco, Vitina; Bianchino, Gabriella; D’Auria, Fiorella; Statuto, Teodora; Mazzoccoli, Carmela; Luca, Luciana De; Petrucci, Maria Teresa; Morabito, Fortunato; Offidani, Massimo; Raimondo, Francesco Di; Falcone, Antonietta; Caravita, Tommaso; Omedè, Paola; Boccadoro, Mario; Palumbo, Antônio; Neri, Antonino

doi:10.1002/ajh.23339

Cited by 64 publications

(65 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…41 Others linked B55a to childhood teratoma, 42 prostate cancer, 43 colorectal cancer, 44 lung cancer, 45 and leukemia. 46 In this study we characterized B55a as a regulator of Plk1 and the DNA damage checkpoint, which finding may mechanistically explain how B55a functions as an important tumor suppressor. After all, it has been well established that dysregulation of Plk1 contributes to cancer progression and resistance, and the DNA damage checkpoint pathway constitutes an important anti-cancer barrier.…”

mentioning

confidence: 82%

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

et al. 2014

View full text Add to dashboard Cite

These authors equally contributed to this work.Keywords: B55a, checkpoint recovery, DNA damage, Plk1, PP2AIn addition to governing mitotic progression, Plk1 also suppresses the activation of the G2 DNA damage checkpoint and promotes checkpoint recovery. Previous studies have shown that checkpoint activation after DNA damage requires inhibition of Plk1, but the underlying mechanism of Plk1 regulation was unknown. In this study we show that the specific phosphatase activity toward Plk1 Thr-210 in interphase Xenopus egg extracts is predominantly PP2A-dependent, and this phosphatase activity is upregulated by DNA damage. Consistently, PP2A associates with Plk1 and the association increases after DNA damage. We further revealed that B55a, a targeting subunit of PP2A and putative tumor suppressor, mediates PP2A/Plk1 association and Plk1 dephosphorylation. B55a and PP2A association is greatly strengthened after DNA damage in an ATM/ATR and checkpoint kinase-dependent manner. Collectively, we report a phosphatase-dependent mechanism that responds to DNA damage and regulates Plk1 and checkpoint recovery.

show abstract

mentioning

confidence: 82%

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

et al. 2014

View full text Add to dashboard Cite

show abstract

“…S5C and S5D). It is worth mentioning that none of the cytogenetic aberrations was associated per se with PFS and OS (15).…”

Section: Clinical Relevance Of Mirna Profiles In Ppclmentioning

confidence: 93%

“…All pPCL cases were investigated by fluorescence in-situ hybridization (FISH) for the major immunoglobulin heavy chain locus (IGH@) translocations and genetic lesions: results are reported in Table 1 and described extensively in ref. 15.…”

Section: Patient Samplesmentioning

confidence: 99%

See 1 more Smart Citation

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

Lionetti

Musto

Martino

et al. 2013

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Primary plasma cell leukemia (pPCL) is a rare and very aggressive form of plasma cell dyscrasia. To date, no information on microRNA (miRNA) expression in pPCL has been reported. This study aimed at investigating the involvement of miRNAs in pPCL and their possible relationship with higher tumor aggressiveness.Experimental design: Global miRNA expression profiles were analyzed in highly purified malignant plasma cells from 18 pPCL untreated patients included in a prospective clinical trial. MiRNA expression patterns were evaluated in comparison with a representative series of multiple myeloma patients, in relation to the most recurrent chromosomal abnormalities (as assessed by fluorescence in situ hybridization and single-nucleotide polymorphism-array analysis), and in association with clinical outcome. MiRNA expression was also integrated with gene expression profiles in pPCL and multiple myeloma samples.Results: We identified a series of deregulated miRNAs in pPCL (42 upregulated and 41 downregulated) in comparison with multiple myeloma. Some of them, on the basis of their reported functions and putative target genes computed by integrative analysis, might have a role in the pathobiology of pPCL. As regards chromosomal aberrations, the expression of some miRNAs mapped to hotspot altered regions was associated with DNA copy number of the corresponding loci. Finally, 4 miRNA (miR-497, miR-106b, miR-181a Ã , and miR-181b) were identified as having expression levels that correlated with treatment response, and 4 (miR-92a, miR-330-3p, miR-22, and miR-146a) with clinical outcome. Conclusions: Overall, our study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations.

show abstract

“…Highly purified (!90%) bone marrow PCs were obtained as previously reported (8). Demographic information and details on molecular alterations of the whole cohort were reported in a previous manuscript aimed at the genomic characterization of the samples (12). Fiftyfive newly diagnosed multiple myeloma patients were included in the study; these cases have been previously reported (13) and were selected on the basis of the representativeness of the main molecular characteristics.…”

Section: Patientsmentioning

confidence: 99%

Transcriptional Characterization of a Prospective Series of Primary Plasma Cell Leukemia Revealed Signatures Associated with Tumor Progression and Poorer Outcome

Todoerti

Agnelli

Fabris

et al. 2013

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Plasma cell leukemia (PCL) is a rare form of plasma cell dyscrasia that presents either as a progression of previously diagnosed multiple myeloma, namely secondary PCL, or as initial manifestation of disease, namely primary PCL (pPCL). Although the presenting signs and symptoms include those seen in multiple myeloma, pPCL is characterized by several aspects that define a more aggressive course. Here, we have investigated the transcriptome of pPCLs and correlated differential expression profiles with outcome to provide insights into the biology of the disease. Experimental Design: The expression profiles of 21 newly diagnosed pPCLs included in a multicenter prospective clinical trial were generated using high-density microarray, then evaluated in comparison with a representative series of patients with multiple myeloma and in association with clinical outcome. Results: All but one of the pPCLs had one of the main immunoglobulin heavy-chain locus translocations, whose associated transcriptional signatures resembled those observed in multiple myeloma. A 503-gene signature distinguished pPCL from multiple myeloma, from which emerged 26 genes whose expression trend was associated with progressive stages of plasma cells dyscrasia in a large dataset from multiple institutions, including samples from normal donors throughout PCL. Finally, 3 genes were identified as having expression levels that correlated with response to the first-line treatment with lenalidomide/dexamethasone, whereas a 27-gene signature was associated with overall survival independently of molecular alterations, hematologic parameters, and renal function. Conclusions: Overall, our data contribute to a fine dissection of pPCL and may provide novel insights into the molecular definition of patients with poorer prognosis. Clin Cancer Res; 19(12); 3247–58. ©2013 AACR.

show abstract

Genome‐wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles

Cited by 64 publications

References 38 publications

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

Transcriptional Characterization of a Prospective Series of Primary Plasma Cell Leukemia Revealed Signatures Associated with Tumor Progression and Poorer Outcome

Contact Info

Product

Resources

About