scholarly journals Identification of an individualized RNA binding protein‐based prognostic signature for diffuse large B‐cell lymphoma

2021 ◽  
Author(s):  
Yongzhi Xie ◽  
Ximei Luo ◽  
Haiqing He ◽  
Tao Pan ◽  
Yizi He
Keyword(s):  
B Cell ◽  
Rna Binding ◽  
Cell Lymphoma ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
B Cell Lymphoma ◽  
Prognostic Signature ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Uncovering the Role of RNA-Binding Protein hnRNP K in B-Cell Lymphomas

2019 ◽  
Vol 112 (1) ◽  
pp. 95-106 ◽  
Author(s):  
Miguel Gallardo ◽  
Prerna Malaney ◽  
Marisa J L Aitken ◽  
Xiaorui Zhang ◽  
Todd M Link ◽  
...  
Keyword(s):  
B Cell ◽  
Rna Binding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hnrnp K ◽  
Large B Cell Lymphoma ◽  
Transgenic Lines ◽  
Large B Cell

Abstract Background Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA-binding protein that is aberrantly expressed in cancers. We and others have previously shown that reduced hnRNP K expression downmodulates tumor-suppressive programs. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon, yet its functional consequences and clinical significance remain unknown. Methods Clinical implications of hnRNP K overexpression were examined through immunohistochemistry on samples from patients with diffuse large B-cell lymphoma who did not harbor MYC alterations (n = 75). A novel transgenic mouse model that overexpresses hnRNP K specifically in B cells was generated to directly examine the role of hnRNP K overexpression in mice (three transgenic lines). Molecular consequences of hnRNP K overexpression were determined through proteomics, formaldehyde-RNA-immunoprecipitation sequencing, and biochemical assays. Therapeutic response to BET-bromodomain inhibition in the context of hnRNP K overexpression was evaluated in vitro and in vivo (n = 3 per group). All statistical tests were two-sided. Results hnRNP K is overexpressed in diffuse large B-cell lymphoma patients without MYC genomic alterations. This overexpression is associated with dismal overall survival and progression-free survival (P < .001). Overexpression of hnRNP K in transgenic mice resulted in the development of lymphomas and reduced survival (P < .001 for all transgenic lines; Line 171[n = 30]: hazard ratio [HR] = 64.23, 95% confidence interval [CI] = 26.1 to 158.0; Line 173 [n = 31]: HR = 25.27, 95% CI = 10.3 to 62.1; Line 177 [n = 25]: HR = 119.5, 95% CI = 42.7 to 334.2, compared with wild-type mice). Clinical samples, mouse models, global screening assays, and biochemical studies revealed that hnRNP K’s oncogenic potential stems from its ability to posttranscriptionally and translationally regulate MYC. Consequently, Hnrnpk overexpression renders cells sensitive to BET-bromodomain-inhibition in both in vitro and transplantation models, which represents a strategy for mitigating hnRNP K-mediated c-Myc activation in patients. Conclusion Our findings indicate that hnRNP K is a bona fide oncogene when overexpressed and represents a novel mechanism for c-Myc activation in the absence of MYC lesions.

Y-box binding protein-1 expression in diffuse large B-cell lymphoma: an impact on prognosis in the rituximab era

2010 ◽  
Vol 51 (11) ◽  
pp. 2054-2062 ◽  
Author(s):  
Kyoko Hanzawa ◽  
Shuji Momose ◽  
Morihiro Higashi ◽  
Michihide Tokuhira ◽  
Reiko Watanabe ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Binding Protein ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Alteration of RhoH Expression Is Associated with Human Diffuse Large B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4298-4298
Author(s):  
Yi Gu ◽  
Carmelita J. Alvares ◽  
Aparna C. Jasti ◽  
Michael Jansen ◽  
Judy Bean ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cell ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Binding Protein ◽  
B Cell Lymphoma ◽  
Cell Development ◽  
Transcript Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract An increasing number of Rho GTPase family proteins have been demonstrated to play critical roles in blood and immune cell development and function. The newly defined RhoH gene has been previously demonstrated to be mutated in lymphoma samples (Dallery et al, 1995; Pasqualucci et al, 2001). These alterations include chromosomal rearrangements and a high frequency of somatic mutations (up to 46%) in human non-Hodgkin’s lymphomas and diffuse large B-cell lymphoma. The RhoH gene encodes a novel hematopoietic-specific member of the RhoE subfamily, which is GTPase deficient, remaining in the active, GTP-bound state. Thus the activity of RhoH is likely regulated by the level of the protein expressed in the cell. The somatic mutations in the RhoH gene have been mapped to a 1.6kb hypermutable region in the intron 1, suggesting the possibility of dysregulated RhoH expression. However, levels of RhoH expression have not been directly measured in these hematopoietic tumors and so it remains unclear whether these mutations translate into aberrant RhoH expression. We utilized quantitative real-time RT-PCR to measure RhoH transcript levels in primary DLBCL patient samples. Based on morphologic and immunophenotypic analysis, 17 DLBCL positive samples and 14 normal control samples were used for our study. The levels of TATA-box binding protein (TBP) and human phosphogycerate kinase (HPGK) cDNAs were also examined simultaneously for relative expression normalization. RhoH transcript levels in a subset of the DLBCL samples were markedly reduced. In particular, 6 of 17 (~35%) tested samples showed a greater than 3-fold reduction in RhoH expression based on both RhoH/TBP and RhoH/HPGK ratios when compared with the median RhoH expression level of 14 normal samples. Overall, RhoH expression levels of the DLBCL group were significantly altered (mainly decreased) as compared with those of the normal group (p < 0.04, student T-test). To further determine correlation of the abnormal RhoH expression with somatic mutations in the hypermutable region of the RhoH gene in the DLBCL samples, we performed genomic PCR amplification and sequencing analysis of this region from the normal and DLBCL samples. In addition, we utilized a computational approach (Trafac - http://trafac.cchmc.org) to identify evolutionarily conserved putative transcription factor binding sites (TFBS) between human and other species in the hypermutable region. 13 conserved TFBS between human and mouse were identified in the hypermutable region. Mutations in the DLBCL patients are localized in 6 of these predicted TFBS, including pancreatic and duodenal homeobox 1 (PDX1), zinc-finger binding protein-89 (ZBP-89), lymphoid enhancer factor 1 (LEF-1), BRIGHT, engrailed 1 and myelin transcription factor 1 (MyT1). Interestingly, LEF-1 and BRIGHT are B cell-specific transcription activators. These results suggest that RhoH expression is frequently altered in 35–40% of DLBCL samples and mutations in the hypermutable region of the RhoH gene in several cases encompass core binding sequences of transcription factors important in B cell development.

scholarly journals A novel prognostic signature based on immune-related genes of diffuse large B-cell lymphoma

Aging ◽  
2021 ◽  
Author(s):  
Zizheng Wu ◽  
Qingpei Guan ◽  
Xue Han ◽  
Xianming Liu ◽  
Lanfang Li ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prognostic Signature ◽  
Large B Cell Lymphoma ◽  
Immune Related Genes ◽  
Large B Cell

scholarly journals Identification of a 14-Gene Prognostic Signature for Diffuse Large B Cell Lymphoma (DLBCL)

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengcheng Feng ◽  
Hongxia Li ◽  
Jinhong Pei ◽  
Yan Huang ◽  
Guixia Li
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
Killer Cell ◽  
B Cell Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Risk Scores ◽  
Prognostic Signature ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Although immunotherapy is a potential strategy to resist cancers, due to the inadequate acknowledge, this treatment is not always effective for diffuse large B cell lymphoma (DLBCL) patients. Based on the current situation, it is critical to systematically investigate the immune pattern. According to the result of univariate and multivariate cox proportional hazards, LASSO regression and Kaplan-Meier survival analysis on immune-related genes (IRGs), a prognostic signature, containing 14 IRGs (AQP9, LMBR1L, FGF20, TANK, CRP, ORM1, JAK1, BACH2, MTCP1, IFITM1, TNFSF10, FGF12, RFX5, and LAP3), was built. This model was validated by external data, and performed well. DLBCL patients were divided into low- and high-risk groups, according to risk scores from risk formula. The results of CIBERSORT showed that different immune status and infiltration pattern were observed in these two groups. Gene set enrichment analysis (GSEA) indicated 12 signaling pathways were significantly enriched in the high-risk group, such as natural killer cell-mediated cytotoxicity, toll-like receptor signaling pathway, and so on. In summary, 14 clinically significant IRGs were screened to build a risk score formula. This formula was an accurate tool to provide a certain basis for the treatment of DLBCL patients.

Y-box-binding protein-1 (YB-1) promotes cell proliferation, adhesion and drug resistance in diffuse large B-cell lymphoma

2016 ◽  
Vol 346 (2) ◽  
pp. 157-166 ◽  
Author(s):  
Xiaobing Miao ◽  
Yaxun Wu ◽  
Yuchan Wang ◽  
Xinghua Zhu ◽  
Haibing Yin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
B Cell ◽  
Cell Lymphoma ◽  
Binding Protein ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

RNA-Binding Protein VICKZ Is Expressed in a Germinal Center Associated Pattern among Lymphoma Subtypes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1909-1909
Author(s):  
Yasodha Natkunam ◽  
Gilad Vainer ◽  
Shuchun Zhao ◽  
Gail Amir ◽  
Eli Pikarsky ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Rna Binding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Recent Effort ◽  
Large B Cell Lymphoma ◽  
Differential Expression Pattern ◽  
Large B Cell

Abstract Recent effort in the molecular characterization of diffuse large B-cell lymphoma (DLBCL) has led to the recognition that patients with DLBCL of germinal center origin exhibit a better overall survival. Thus, identification and characterization of markers of germinal center derivation are of importance in dissecting prognostic subclasses of DLBCL. The VICKZ (Vg1 RBP/Vera, IMP1, 2, 3, CRD-BP, KOC, ZBP-1) family members are RNA-binding proteins that recognize specific RNA targets and have been implicated in diverse cellular functions including cell polarity, migration, proliferation and tumorigenesis/metastasis. We generated an antibody that recognizes all three isoforms of VICKZ protein and characterized its expression in normal lymphoid tissue and in lymphoma subtypes. In normal tonsils, VICKZ protein showed a germinal center-specific pattern of expression with staining localized to the cytoplasm. Among 868 non-Hodgkin and Hodgkin lymphomas tested by immunohistochemistry on tissue microarrays, staining for VICKZ protein was present in 76% (126/165) of follicular lymphoma, 78% (155/200) of DLBCL, 90% (9/10) of mediastinal large B-cell lymphoma, and 100% (2/2) of Burkitt lymphoma. A subset of mantle cell lymphoma (11%, 2/19), extranodal (8%, 2/25), and nodal (20%, 1/5) marginal zone lymphoma and lymphoblastic lymphoma (25%, 4/13), showed VICKZ staining. The majority of lymphocyte predominant Hodgkin (92%, 12/13) and classical Hodgkin (94%, 101/108) lymphoma were found to be positive. Among T cell lymphoma, anaplastic large cell lymphoma were positive (75%, 6/9). Additional work is in progress to correlate VICKZ protein expression with other germinal center markers such as HGAL, BCL6 and CD10 as well as with prognostic subclasses of DLBCL. The differential expression pattern of VICKZ protein in lymphoma subtypes suggests a potential utility for VICKZ in the identification of subgroups of DLBCL associated with different prognoses.

scholarly journals Expression and phosphorylation of translation regulatory protein 4E-binding protein (BP)-1 in low-risk diffuse large B cell lymphoma

2013 ◽  
Vol 6 (3) ◽  
pp. 121-126
Author(s):  
Mary J. Ninan ◽  
Ajay Rawal ◽  
Hector Mesa ◽  
Dennis J. Knapp ◽  
Michael A. Kuskowski ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Binding Protein ◽  
Regulatory Protein ◽  
B Cell Lymphoma ◽  
Low Risk ◽  
Large B Cell Lymphoma ◽  
Large B Cell
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