Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma

Iqbal, Javeed; Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M.; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Smith, Lynette M.; Wright, George W.; Bhagavathi, Sharathkumar; Dybkær, Karen; Fu, Kai; Greiner, Timothy C.; Vose, Julie M.; Jaffe, Elaine S.; Rimsza, Lisa M.; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elı́as; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Armitage, Jamés O.; Weisenburger, Dennis D.; Staudt, Louis M.; Gascoyne, Randy D.; McKeithan, Timothy W.; Chan, Wing C.

doi:10.1182/blood-2014-04-566778

Cited by 111 publications

(118 citation statements)

References 49 publications

(57 reference statements)

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“…Their miR-155 expression levels were 33.0, 30.0 and 17.0. Also, another BL case with miR-155 expression level of 26.0 was died after the first cycle of therapy which was consistent with previous study performed by Iqpal et al [38]. These findings mean that miR-155 does not act as tumor suppressor gene in BL because of the bad prognosis that accompanying BL cases who were expressing increased levels of miR-155.…”

Section: Discussionsupporting

confidence: 89%

“…Their mean fold-change values had spanned from 3 to 19 in patients with DLBCL [29][30][31][32][33][34][35][36][37]. As well, a lot of studies have found down regulation of miR-155 expression levels within BL versus CLL, MCL and FL [38,39]. Contrary, the studies of Eis et al [40] and Metzler [41] showed that miR-155 was up-regulated in pediatric burkitt's lymphoma which is opposite to what was shown in ours.…”

Section: Discussioncontrasting

confidence: 71%

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Expression Signature of MicroRNA-155 and its Association with Response to Treatment within Different Subtypes of B-Cell Malignancies

Eldin¹,

Naem²,

Higazi³

et al. 2017

Biol Med (Aligarh)

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Objectives: Emerging evidence suggests that microRNAs could serve as non-invasive biomarkers for cancer patients. However, they are mostly not fully investigated as biomarkers in the classification, progression and prognosis of different cancers. Our study was designed to explore the microRNA-155 (miR-155) expression levels in peripheral blood mononuclear cells (PBMCs) in patients with various subtypes of B-cell malignancies. Also, we aimed to correlate between miR-155 expression levels and the diverse clinico-pathologic features as well as the prognostic fate of these patients after treatment completion. Subjects and methods:Using whole blood samples from 53 patients with B-cell malignancies and 15 apparently healthy subjects, miR-155 was extracted and profiled by quantitative real-time PCR (RT-qPCR). The B-cell malignancies patients were including 22 diffuse large B-cell lymphoma (DLBCL), 15 chronic lymphocytic leukemia (CLL), 9 follicular lymphoma patients (FL) and 7 subjects with burkitt′s lymphoma (BL). The samples were withdrawn before starting chemotherapy in addition to after completing their therapeutic courses by 6 months. Subsequently, the patients were further sub-grouped into those with partial remission, complete remission, resistant disease and relapse. Results:We found that miR-155 expression levels differentiate lymphoma entities from normal subjects (p ≤ 0.001) and its expression fold changes distinguish B-cell lymphoma subtypes from each other's (p<0.05). In addition, miR-155 was significantly correlated with age and LDH levels. The receiver operating curve (ROC) was employed to identify the diagnostic outcomes of miR-155 in discriminating B-cell malignancies entities from each other's (AUC=0.957 for DLBCL vs. CLL+FL and AUC=1.000 for CLL vs. FL). Otherwise, when BL was versus healthy controls the AUC was equal to 0.552. As well, we demonstrated an association between elevated miR-155 expression levels and poor response to treatment with increased cases of relapse, partial remission or resistance to treatment. Conclusions:This study suggests that miR-155 has an expression profile that differs according to B-cell malignancies subtype. Besides, miR-155 expression levels may modulate the patient's response to treatment. These results support a role for miR-155 to provide helpful diagnostic/prognostic information in B-cell malignancies and may highlight novel pathways to be targeted for therapeutics in the future.

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Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 71%

Expression Signature of MicroRNA-155 and its Association with Response to Treatment within Different Subtypes of B-Cell Malignancies

Eldin¹,

Naem²,

Higazi³

et al. 2017

Biol Med (Aligarh)

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“…Other studies have shown these microRNAs to be regulated by the Myc, Bcl-6, STAT3, and NF-κB pathways, and the MIR17HG locus was frequently amplified in Burkitt lymphoma. [45][46][47][48] Downregulation of MIR155HG expression may contribute to the pathogenesis of MYC translocation, as miR-155 suppresses activation-induced cytidine deaminase, which mediates MYC/IGH translocation. 49 These microRNA signatures may also be implicated in defining the gene expression profiling features of MYC-R + /Myc high GCB-DLBCL.…”

Section: Discussionmentioning

confidence: 99%

“…In lymphoma cells, ectopic expression of miR-155 is associated with downregulation of IGJ, FAS, SMAD3/5, and BACH1, as well as HLA genes. 45 IGJ, FAS, and genes involved in BMP/SMAD pathways (such as SMAD1, BMP3, and BMP7), as well as SMARCA4 (miR-21 target gene 50 ), were upregulated in MYC-R + GCB-DLBCL (Tables 3 and 5). miR-155 target gene BCL2 showed increased Bcl-2 protein expression in ABC-DLBCL (Figure 3c).…”

Section: Discussionmentioning

confidence: 99%

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

et al. 2015

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MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n = 344) and Myc expression (n = 535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall

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“…A four-microRNA signature comprising miR-486, miR-30d, miR-1 and miR-499 in the serum independently predicts survival of non-small cell lung cancer, showing potential of microRNAs as noninvasive prognosis predictor [85]. In a recent study, high expression levels of miR-155 were significantly associated with therapeutic resistance of patients with diffuse large B-cell lymphoma to the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone treatment [86]. These microRNA indicators for therapeutic response may help stratify patients for anticancer treatment to avoid unnecessary treatments.…”

Section: Potential Use Of Microrna As Cancer Biomarkersmentioning

confidence: 99%

Non-coding RNAs: the cancer genome dark matter that matters!

Ling¹,

Girnita

Buda

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Protein-coding genes comprise only 3% of the human genome, while the genes that are transcribed into RNAs but do not code for proteins occupy majority of the genome. Once considered as biological darker matter, non-coding RNAs are now being recognized as critical regulators in cancer genome. Among the many types of non-coding RNAs, microRNAs approximately 20 nucleotides in length are best characterized and their mechanisms of action are well generalized. microRNA exerts oncogenic or tumor suppressor function by regulation of protein-coding genes via sequence complementarity. The expression of microRNA is aberrantly regulated in all cancer types, and both academia and biotech companies have been keenly pursuing the potential of microRNA as cancer biomarker for early detection, prognosis, and therapeutic response. The key involvement of microRNAs in cancer also prompted interest on exploration of therapeutic values of microRNAs as anticancer drugs and drug targets. MRX34, a liposome-formulated miRNA-34 mimic, developed by Mirna Therapeutics, becomes the first microRNA therapeutic entering clinical trial for the treatment of hepatocellular carcinoma, renal cell carcinoma, and melanoma. In this review, we presented a general overview of microRNAs in cancer biology, the potential of microRNAs as cancer biomarkers and therapeutic targets, and associated challenges.

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Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma

Abstract: Key Points Well-defined miRNA signatures for normal B-cell subsets and their malignant counterparts including BL and DLBCL subgroups were identified. In DLBCL, miRNA-155 expression is associated with R-CHOP resistance, but in vitro sensitivity to AKT pathway inhibition.

Cited by 111 publications

References 49 publications

Expression Signature of MicroRNA-155 and its Association with Response to Treatment within Different Subtypes of B-Cell Malignancies

Expression Signature of MicroRNA-155 and its Association with Response to Treatment within Different Subtypes of B-Cell Malignancies

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

Non-coding RNAs: the cancer genome dark matter that matters!

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