Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia

Lloveras, Elisabet; Granada, Isabel; Zamora, Lurdes; Espinet, Blanca; Florensa, Lourdes; Besses, Carles; Xandri, Marisol; Pérez-Vila, Maria Encarnación; Millá, Fuensanta; Woessner, S; Solé, Françesc

doi:10.1016/s0165-4608(03)00233-4

Cited by 18 publications

(23 citation statements)

References 27 publications

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“…Only three patients in both studies had hyperdiploidy (48,49, and 51 and 47, 54 and 86 chromosomes respectively). These results are in contrast with those published in MM, [27][28][29] in which hyperdiploidy is observed in approximately 60% of patients, but they confirm previously published analyses in PCL [8,30]. Analysis of rearrangements of the 14q32 region by FISH revealed significant differences with high cell mass MM-a higher incidence of t(11;14) (33 vs. 16%; p \ .025) and of t(14;16) (13 vs. 1%; p \ .002) though incidences of t(4;14) were identical and a higher incidence of monosomy 13 (68 vs. 42%; p = .005) [24].…”

Section: Genetic Changes and Pclsupporting

confidence: 80%

“…Eleven percent of PPCL and 33% of SPCL tumors showed biallelic inactivation of TP53 with simultaneous allelic deletion and mutation. Interestingly, monoallelic or biallelic inactivation of TP53 did not correlate significantly with survival in SPCL, unlike MM, where-17p13.1 predicts adverse survival [30,32]. Lack of correlation between TP53 status and survival may reflect ubiquitous targeting of the p53 pathway in SPCL.…”

Section: The P53 Inactivationmentioning

confidence: 91%

“…Moreover, TP53 deletion was complemented by functionally relevant TP53 coding mutations in 24% of PCL patients tested, contributing to a substantial prevalence of allelic TP53 inactivation of 56% in PPCL and 83% in SPCL. The high prevalence of TP53 inactivation in de novo PPCL is surprising; in MM 17p13.1 deletion is a late event found only in 10% of tumors [30][31][32] and TP53 coding mutations are rare (3%) [33]. Eleven percent of PPCL and 33% of SPCL tumors showed biallelic inactivation of TP53 with simultaneous allelic deletion and mutation.…”

Section: The P53 Inactivationmentioning

confidence: 99%

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Plasma cell leukemia: a highly aggressive monoclonal gammopathy with a very poor prognosis

Jiménez-Zepeda

Dominguez-Martinez

2009

Int J Hematol

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Plasma cell leukemia (PCL) is an aggressive variant of multiple myeloma and is characterized by the presence of >20% and/or an absolute number of greater 2 x 10(9)/L plasma cells circulating in the peripheral blood. PCL represents approximately 2-4% of all MM diagnosis and exists in two forms: primary PCL (PPCL, 60% of cases) presents de novo, whereas secondary PCL (SPCL, accounts for the remaining 40%) consists of a leukemic transformation in patients with a previously diagnosed MM. Because the mechanisms contributing to the pathogenesis of PCL are not fully understood, immunophenotyping, genetic evaluation (conventional karyotype, FISH, GEP and array-CGH), and immunohistochemistry are really important tools to investigate why plasma cells escape from bone marrow and become highly aggressive. Since treatment with standard agents and steroids is poorly effective, a combination of new drugs as part of the induction regimens and bone marrow transplant (autologous and allogeneic approaches) could nearly overcome the poor prognosis exhibited by PCL patients.

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Section: Genetic Changes and Pclsupporting

confidence: 80%

Section: The P53 Inactivationmentioning

confidence: 91%

Section: The P53 Inactivationmentioning

confidence: 99%

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Plasma cell leukemia: a highly aggressive monoclonal gammopathy with a very poor prognosis

Jiménez-Zepeda

Dominguez-Martinez

2009

Int J Hematol

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“…While 13% of MM patients carry TP53 coding mutations or 17q13.1 deletion causing allelic loss of TP53, 24% of plasma cell leukemia (PCL) patients have TP53 coding mutations and 50% of primary PCL patients or 75% of secondary PCL patients have 17q13.1 deletion (47–50). Furthermore, a biallelic inactivation with both coding mutation and allelic deletion has been found in 11% and 33% of primary or secondary PCL patients, respectively (47, 49, 51), suggesting that the “biologically end-stage” disease might benefit from therapies restoring the TP53 function through miR-34a enforcement.…”

Section: Discussionmentioning

confidence: 99%

Synthetic miR-34a Mimics as a Novel Therapeutic Agent for Multiple Myeloma:In VitroandIn VivoEvidence

Martino

Leone

Amodio

et al. 2012

Clinical Cancer Research

214

182

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Purpose Deregulated expression of microRNAs (miRNAs) has been demonstrated in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a. Experimental Design Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo. Results Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6 and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in SCID mice. The anti-MM activity of lipidic-formulated miR-34a was further demonstrated in vivo in two different experimental settings: i) SCID mice bearing non-transduced MM xenografts; and ii) SCID-synth-hu mice implanted with synthetic 3D scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity. Conclusions Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.

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“…Examples of secondary events are deletion or inactivation of TP53 and activation of proto-oncogenes c-MYC , N-RAS and K-RAS [11], deletion of PTEN [12] and Rb [13]. Interestingly, unlike MM, monoallelic or biallelic inactivation of TP53 does not correlate with survival [14, 15], suggesting ubiquitous targeting of the p53 pathway in sPCL [16]. Immunophenotypic profiling of PCL versus MM cells suggests that modulated expression of some surface antigens might contribute to the escape from the bone marrow environment and also from immunological surveillance, including down-regulation of CD11a/b and CD18 [17] and CD56.…”

Section: Introductionmentioning

confidence: 99%

Proteome alterations associated with transformation of multiple myeloma to secondary plasma cell leukemia

et al. 2016

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Plasma cell leukemia is a rare and aggressive plasma cell neoplasm that may either originate de novo (primary PCL) or by leukemic transformation of multiple myeloma (MM) to secondary PCL (sPCL). The prognosis of sPCL is very poor, and currently no standard treatment is available due to lack of prospective clinical studies. In an attempt to elucidate factors contributing to transformation, we have performed super-SILAC quantitative proteome profiling of malignant plasma cells collected from the same patient at both the MM and sPCL stages of the disease. 795 proteins were found to be differentially expressed in the MM and sPCL samples. Gene ontology analysis indicated a metabolic shift towards aerobic glycolysis in sPCL as well as marked down-regulation of enzymes involved in glycan synthesis, potentially mediating altered glycosylation of surface receptors. There was no significant change in overall genomic 5-methylcytosine or 5-hydroxymethylcytosine at the two stages, indicating that epigenetic dysregulation was not a major driver of transformation to sPCL. The present study constitutes the first attempt to provide a comprehensive map of the altered protein expression profile accompanying transformation of MM to sPCL in a single patient, identifying several candidate proteins that can be targeted by currently available small molecule drugs. Our dataset furthermore constitutes a reference dataset for further proteomic analysis of sPCL transformation.

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Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia

Cited by 18 publications

References 27 publications

Plasma cell leukemia: a highly aggressive monoclonal gammopathy with a very poor prognosis

Plasma cell leukemia: a highly aggressive monoclonal gammopathy with a very poor prognosis

Synthetic miR-34a Mimics as a Novel Therapeutic Agent for Multiple Myeloma:In VitroandIn VivoEvidence

Proteome alterations associated with transformation of multiple myeloma to secondary plasma cell leukemia

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