Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment

Guo, Lingchuan; Lin, Pei; Xiong, Hui; Tu, Shichun; Chen, Gang

doi:10.1016/j.bbcan.2018.01.001

Cited by 15 publications

(15 citation statements)

References 143 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FL initially presents with a slow progression but eventually 40–50% of these cancers transform into aggressive forms of DLBCL ( 1 ). Although with chemo- and immuno- therapy DLBCL cures can be achieved, many patients are still refractory and succumb to progressive or relapsed disease ( 2 ). Both FL and DLBCL derive from B cells that undergo the germinal center (GC) reaction, where B cells are generated and selected to produce high affinity antibodies ( 3 – 5 ).…”

Section: Introductionmentioning

confidence: 99%

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas

et al. 2020

View full text Add to dashboard Cite

Somatic mutations affecting CREBBP and EP300 are a hallmark of Diffuse Large B Cell Lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small molecule inhibitors of CARM1 in DLBCL and other cancers.

show abstract

Section: Introductionmentioning

confidence: 99%

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas

et al. 2020

View full text Add to dashboard Cite

show abstract

“…1 Diffuse large B cell lymphoma is a group of heterogeneous tumors, 2 with differences in terms of gene alterations, clinical features, morphological manifestations, responses to treatment and prognoses. [3][4][5] Although most patients with DLBCL can be cured with 6-8 cycles of R-CHOP chemotherapy, there remain 10%-15% of patients with DLBCL who have primary resistance and 20%-30% of patients suffer recurrences. 6 Therefore, to find new treatments for DLBCL, a program is required to control the progression of the disease, possibly constituting a new strategy for the treatment of cancer.…”

Section: Introductionmentioning

confidence: 99%

Effect of BCLAF1 on HDAC inhibitor LMK-235-mediated apoptosis of diffuse large B cell lymphoma cells and its mechanism

Cheng

et al. 2018

Cancer Biology & Therapy

View full text Add to dashboard Cite

Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma. It is a group of malignant tumors with a large number of clinical manifestations and prognoses. Therefore, it is necessary to explore its unknown potential therapeutic targets. Histone deacetylase inhibitor (HDACi) is a novel drug for the treatment of DLBCL, however pan-HDACis cannot be ignored because of their clinical efficacy. By contrast, specific HDACi is well-tolerated, and LMK-235 is a novel HDACi that is a specific inhibitor of HDAC4 and HDAC5. In this study, we investigated the up-regulation of BCLAF1 through NF-κB signaling pathways in LMK-235, mediating the apoptosis of two diffuse large B-cell lymphoma cell lines, OCI-LY10 and OCI-LY3. Further studies showed that BCLAF1 expression was increased in DLBCL cells after treatment with the NF-κB inhibitor Bay11-7082. The combination of Bay11-7082 and siRNA si-HDAC4 significantly increased BCLAF1 expression and further increased apoptosis. These results indicate that BCLAF1 plays an important role in LMK-235-mediated apoptosis and may be a potential target for the treatment of diffuse large B-cell lymphoma.

show abstract

“…More recently, alternative classification schemes have emerged that additionally incorporate DNA mutational patterns, which in some studies has been shown to provide greater prognostic information than mRNA expression signatures alone . As well, whole exome sequencing has been used as a measure of intratumoral heterogeneity in DLBCL, with greater heterogeneity being linked with worse outcome . Each of these prior approaches have relied upon characterization of tumor cells in bulk and is thus unable to resolve potential phenotypic variation among individual cells within tumors.…”

mentioning

confidence: 99%

Single Cell Phenotypic Profiling of 27 DLBCL Cases Reveals Marked Intertumoral and Intratumoral Heterogeneity

et al. 2019

View full text Add to dashboard Cite

Diffuse large B‐cell lymphoma (DLBCL) is the most common histologic subtype of non‐Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell‐of‐origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B‐cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B‐cells from each patient occupied unique regions in 37‐dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case, we were able to demonstrate direct correspondence between protein‐level phenotypic subsets and DNA mutation‐defined subclones. In summary, CyTOF analysis can resolve both intertumoral and intratumoral heterogeneity among primary samples and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones. © 2019 International Society for Advancement of Cytometry

show abstract

Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment

Cited by 15 publications

References 143 publications

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas

Effect of BCLAF1 on HDAC inhibitor LMK-235-mediated apoptosis of diffuse large B cell lymphoma cells and its mechanism

Single Cell Phenotypic Profiling of 27 DLBCL Cases Reveals Marked Intertumoral and Intratumoral Heterogeneity

Contact Info

Product

Resources

About