Cytogenetic and Flow Cytometry Evaluation of Richter Syndrome Reveals MYC, CDKN2A, IGH Alterations With Loss of CD52, CD62L and Increase of CD71 Antigen Expression as the Most Frequent Recurrent Abnormalities

Woroniecka, Renata; Rymkiewicz, Grzegorz; Grygalewicz, Beata; Błachnio, Katarzyna; Rygier, Jolanta; Jarmuż-Szymczak, Małgorzata; Ratajczak, Błażej; Pieńkowska-Grela, Barbara

doi:10.1309/ajcpatrqwanw2o3n

Cited by 30 publications

(25 citation statements)

References 37 publications

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“…We examined the expression of MYC gene and indeed found elevated levels using both GEP (1.4 and 1.1), and qPCR (4.59). Alterations of MYC gene have been repeatedly associated with RS . Other mutations with reported connection to prognosis that were enriched in the MCL clone included SF3B1 , CREBBP and NUP214 genes.…”

Section: Discussionmentioning

confidence: 98%

Mantle cell lymphoma‐variant Richter syndrome: Detailed molecular‐cytogenetic and backtracking analysis reveals slow evolution of a pre‐MCL clone in parallel with CLL over several years

Klener

Froňková

Berkova

et al. 2016

Intl Journal of Cancer

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Richter syndrome represents the transformation of the chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most frequently the diffuse large B-cell lymphoma (DLBCL). In this report we describe a patient with CLL, who developed a clonally-related pleomorphic highly-aggressive mantle cell lymphoma (MCL) after five cycles of a fludarabine-based second-line therapy for the first relapse of CLL. Molecular cytogenetic methods together with whole-exome sequencing revealed numerous gene alterations restricted to the MCL clone (apart from the canonical t(11;14)(q13;q32) translocation) including gain of one copy of ATM gene or emergence of TP53, CREBBP, NUP214, FUBP1 and SF3B1 gene mutations. Similarly, gene expression analysis revealed vast differences between the MCL and CLL transcriptome, including overexpression of cyclin D1, downregulation of cyclins D2 and D3, or downregulation of IL4R in the MCL clone. Backtracking analysis using quantitative PCR specifically detecting an MCL-restricted focal deletion of TP53 revealed that the pre-MCL clone appeared in the bone marrow and peripheral blood of the patient approximately 4 years before the clinical manifestation of MCL. Both molecular cytogenetic and sequencing data support the hypothesis of a slow development of the pre-MCL clone in parallel to CLL over several years, and thereby exclude the possibility that the transformation event occurred at the stage of the CLL relapse clone by mere t(11;14)(q13;q32) acquisition.

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Section: Discussionmentioning

confidence: 98%

Mantle cell lymphoma‐variant Richter syndrome: Detailed molecular‐cytogenetic and backtracking analysis reveals slow evolution of a pre‐MCL clone in parallel with CLL over several years

Klener

Froňková

Berkova

et al. 2016

Intl Journal of Cancer

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“…Immunophenotype was also determined by flow cytometry of cellular suspension obtained by fine needle aspiration biopsy or by ultrasound-guided fine needle aspiration biopsy (cases with bulky abdominal mass, stomach, and abdominal lymph node involvement) of the involved lymph nodes, tonsils, and extranodal tumors performed by a hematopathologist. Cells from patients with histopathologically confirmed or suspected of Burkitt lymphoma, were incubated with a panel of monoclonal antibodies 1,4,12 (for staining procedure and a list of antibodies see Supplementary Methods and Supplementary Table 2). Antigen expression ( Figures 2 and 3, and Supplementary Table 4) was quantified by FACSCalibur and FACSCanto II cytometers (Becton Dickinson, BD), and was categorized according to the percentages of positive cells into three groups, marked: '(-)'no expression (o 20% of neoplastic cells), '(+/-)'expression in 420% but o 100% of cells, and '(+)'in 100% of lymphoma cells.…”

Section: Flow Cytometry Immunophenotyping Cytology and Cell Stainingmentioning

confidence: 99%

“…This approach enables to quantify the expression of a given antigen as higher (+)↑ or weaker (+)↓ in Burkitt-like lymphoma with 11q aberration and in Burkitt lymphoma cells than in control lymphocytes, as well as to compare the expression of pan-B antigens in Burkittlike lymphoma with 11q aberration and Burkitt lymphoma cells (ie, CD19 vs CD20 vs CD22, using monoclonal antibodies conjugated with the same fluorochrome), as described. 1,4,12 'Dim' (lower and heterogeneous) or 'bright' (higher and homogeneous) expression was defined as previously. 4,12 Simultaneously, cytological smears were stained with a hematoxylin-eosin and May-Grünwald-Giemsa for morphological evaluation (Figure 2a).…”

Section: Flow Cytometry Immunophenotyping Cytology and Cell Stainingmentioning

confidence: 99%

A comprehensive flow-cytometry-based immunophenotypic characterization of Burkitt-like lymphoma with 11q aberration

et al. 2018

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We previously described a subset of MYC translocation-negative aggressive B-cell lymphomas resembling Burkitt lymphoma, characterized by proximal gains and distal losses in chromosome 11. In the 2016 WHO classification, these MYC-negative lymphomas were recognized as a new provisional entity, 'Burkitt-like lymphoma with 11q aberration'. Here we present an immunophenotype analysis of Burkitt-like lymphomas with 11q aberration. Cells were acquired by fine needle aspiration biopsy from 10 young adult patients, 80% of whom presented recurrence-free 5-year survival. Twenty-three MYC-positive Burkitt lymphomas, including three carrying both MYC rearrangement and 11q aberration, served as controls. By immunohistochemistry, all Burkitt-like lymphomas with 11q aberration were CD20+/CD10+/BCL6+/BCL2-/MUM1-/MYC+/EBV-, usually LMO2+/CD44-/CD43- and sometimes CD56+, and showed high proliferation rate. By flow cytometry, Burkitt-like lymphoma with 11q aberration immunophenotypically resembled MYC-positive Burkitt lymphoma, except for significantly (adjusted P<0.001) more frequent CD38 expression in Burkitt lymphoma (91% MYC-positive Burkitt lymphoma vs 10% Burkitt-like lymphoma with 11q aberration), more frequently diminished CD45 expression in Burkitt lymphoma (74% vs 10%), an exclusive CD16/CD56 and highly restricted CD8 expression in Burkitt-like lymphoma with 11q aberration (60% vs 0% and 40% vs 4%, respectively). We showed high diagnostic accuracy and effectiveness of flow cytometry in Burkitt lymphoma. CD16/CD56 expression without CD38 and the lack of CD16/CD56 with CD38 expression proves to be a reliable, fast, and cost-effective method for diagnosing 11q aberration and MYC rearrangements in CD10(+) aggressive lymphomas, respectively. In addition, we confirmed a pattern of an inverted duplication with telomeric loss of 11q, as a recurrent 11q abnormality, but one case presented alternative changes, possibly resulting in an equivalent molecular effect. Our findings reveal similarities along with subtle but essential differences in the immunophenotype of Burkitt-like lymphoma with 11q aberration and MYC-positive Burkitt lymphoma, important for the differential diagnosis, but also for understanding the pathogenesis of Burkitt-like lymphoma with 11q aberration.

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“…In most RS cases, MYC aberrations were found, but it is still not clear whether MYC aberration is the trigger of disease progression or one of the events contributing to the already induced progression. Nevertheless, the association of MYC translocation with an unfavorable prognosis of CLL/Richter syndrome patients was confirmed in several studies [1,66,67]. …”

Section: Aberrant Myc Signaling Pathways In B Cell Lymphomagenesismentioning

confidence: 92%

Role of MYC in B Cell Lymphomagenesis

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et al. 2017

Genes

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B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

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Cytogenetic and Flow Cytometry Evaluation of Richter Syndrome Reveals MYC, CDKN2A, IGH Alterations With Loss of CD52, CD62L and Increase of CD71 Antigen Expression as the Most Frequent Recurrent Abnormalities

Cited by 30 publications

References 37 publications

Mantle cell lymphoma‐variant Richter syndrome: Detailed molecular‐cytogenetic and backtracking analysis reveals slow evolution of a pre‐MCL clone in parallel with CLL over several years

Mantle cell lymphoma‐variant Richter syndrome: Detailed molecular‐cytogenetic and backtracking analysis reveals slow evolution of a pre‐MCL clone in parallel with CLL over several years

A comprehensive flow-cytometry-based immunophenotypic characterization of Burkitt-like lymphoma with 11q aberration

Role of MYC in B Cell Lymphomagenesis

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