Dataset Information

Immunophenotypic Landscape and Prognosis of Diffuse Large B-Cell Lymphoma with MYC/BCL2 Double Expression: An Analysis of A Prospectively Immunoprofiled Cohort.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (P = 0.058). DE-DLBCL patients were older (P = 0.040) and more frequently exhibited elevated serum LDH levels (P = 0.002), higher international prognostic index (IPI; P = 0.042), non-germinal-center B-cell phenotype (P < 0.001), and poor response to therapy (P = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI (P < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; P = 0.017), involvement of ³2 extranodal sites (P = 0.021), bone marrow involvement (P = 0.001), high IPI (P = 0.017), CD10 expression (P = 0.006), poor performance status (P = 0.028), and elevated LDH levels (P < 0.001) were significantly associated with poor OS. Notably, DE-DLBCL patients with normal LDH levels exhibited similar PFS and OS to those of patients with non-DE-DLBCL. Our findings suggest that MYC/BCL2 DE predicts poor prognosis in DLBCL. Risk stratification of DE-DLBCL patients based on LDH levels may guide clinical decision-making for DE-DLBCL patients.

SUBMITTER: Han B

PROVIDER: S-EPMC7697982 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Immunophenotypic Landscape and Prognosis of Diffuse Large B-Cell Lymphoma with MYC/BCL2 Double Expression: An Analysis of A Prospectively Immunoprofiled Cohort.

Han Bogyeong B Kim Sehui S Koh Jiwon J Yim Jeemin J Lee Cheol C Heo Dae Seog DS Kim Tae Min TM Paik Jin Ho JH Jeon Yoon Kyung YK

Cancers 20201109 11

Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (P = 0.058). DE-DLBCL patients ...[more]

PMID: 33182440

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Project description:BACKGROUND:The poor outcome of high-grade B-cell lymphoma, with rearrangements of MYC, BCL2 and/or BCL6, also known as double-hit lymphoma or triple-hit lymphoma (DHL or THL), has been well documented, while the clinical significance of extra copies of MYC, BCL2 or BCL6 are still less well known. METHODS:In total, 130 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) were included in our study. Fluorescence in situ hybridization and immunohistochemistry were performed in all cases to evaluate the genetic status and protein expression levels of MYC, BCL2 and BCL6. RESULTS:Among the 130 cases of DLBCL, the prevalence rates of extra copies of MYC, BCL2 and BCL6 were 10.8, 20.0 and 14.6%, respectively, and the corresponding rates of gene rearrangement were 10.0, 14.6 and 16.9%, respectively. In total, 7.7% (10/130) of patients were DHL/THL; 9.2% (12/130) of patients were DLBCL with MYC and BCL2 and/or BCL6 gene abnormalities including rearrangements or extra copies, while excluded DHL/THL. The positive protein expression rates of MYC, BCL2 and BCL6 were 46.9% (61), 75.4% (98) and 70.0% (91), respectively. Among the 51 cases with MYC/BCL2 co-expression, 14 cases showed concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities, and the remaining 37 cases were classified as double-expressor lymphoma (DEL). MYC and BCL2 rearrangement and BCL2 extra copies were all associated with upregulated protein expression. Cases with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities were both associated with MYC/BCL2 co-expression. Patients with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities excluded DHL/THL had shorter OS (P?<?0.001) than patients with DLBCL with no genetic change, and showed no statistical different with patients with DHL/THL (P?=?0.419). Extra copies of MYC was independent prognostic factors for DLBCL. CONCLUSIONS:Patients with MYC and BCL2 and/or BCL6 gene extra copies might show a trend towards poor prognosis, and the detection of extra copies of MYC, BCL2 and BCL6 might deserve more attention.

Project description:Double-hit (DH) or double-expresser (DE) lymphomas are high-grade diffuse large B-cell lymphomas (DLBCL) that are mostly incurable with standard chemo-immunotherapy due to treatment resistance. The generation of drug-induced aneuploid/polyploid (DIAP) cells is a common effect of anti-DLBCL therapies (e.g. vincristine, doxorubicin). DIAP cells are thought to be responsible for treatment resistance, as they are capable of re-entering the cell cycle during off-therapy periods. Previously we have shown that combination of alisertib plus ibrutinib plus rituximab can partially abrogate DIAP cells and induce cell death. Here, we provide evidence that DIAP cells can re-enter the cell cycle and escape cell death during anti-DLBCL treatment. We also discuss MYC/BCL2 mediated molecular mechanism that underlie treatment resistance. We isolated aneuploid/polyploid populations of DH/DE-DLBCL cells after treatment with the aurora kinase (AK) inhibitor alisertib. Time-lapse microscopy of single polyploid cells revealed that following drug removal, a subset of these DIAP cells divide and proliferate by reductive cell divisions, including multipolar mitosis, meiosis-like nuclear fission and budding. Genomic, proteomic, and kinomic profiling demonstrated that alisertib-induced aneuploid/polyploid cells up-regulate DNA damage, DNA replication and immune evasion pathways. In addition, we identified amplified receptor tyrosine kinase and T-cell receptor signaling, as well as MYC-mediated dysregulation of the spindle assembly checkpoints RanGAP1, TPX2 and KPNA2. We infer that these factors contribute to treatment resistance of DIAP cells. These findings provide opportunities to develop novel DH/DE-DLBCL therapies, specifically targeting DIAP cells. Key Points:? MYC mediated upregulation of TPX2, KPNA2 and RanGAP1 dysregulate the spindle assembly checkpoint in drug-induced polyploid cells.? Drug-induced polyploid cells re-enter the cell cycle via multipolar mitosis, fission or budding, a mechanism of disease relapse.

Dataset Information

Immunophenotypic Landscape and Prognosis of Diffuse Large B-Cell Lymphoma with MYC/BCL2 Double Expression: An Analysis of A Prospectively Immunoprofiled Cohort.

Publications

Immunophenotypic Landscape and Prognosis of Diffuse Large B-Cell Lymphoma with MYC/BCL2 Double Expression: An Analysis of A Prospectively Immunoprofiled Cohort.

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