miR-15b/16-2 deletion promotes B-cell malignancies Lovat, Francesca; Fassan, Matteo; Gasparini, Pierluigi ...
Proceedings of the National Academy of Sciences - PNAS,
09/2015, Letnik:
112, Številka:
37
Journal Article
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The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over two-thirds of B-cell chronic lymphocytic leukemia characterized by the ...deletion of the miR-15a/16-1 locus at 13q14. Despite the well-established understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster’s role in vivo. These mice developed B-cell malignancy by age 15–18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates theCCND2(Cyclin D2),CCND1(Cyclin D1), andIGF1R(insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.
AIM：To compare the reliability of gastritis staging sys-tems in ranking gastritis-associated cancer risk in a large series of consecutive patients.METHODS：Gastric mucosal atrophy is the precancer-ous ...condition in which intestinal-type gastric cancer（GC）most frequently develops.The operative link for gas-tritis assessment（OLGA）staging system ranks the GC risk according to both the topography and the severity of gastric atrophy（as assessed histologically on the ba-sis of the Sydney protocol for gastric mucosal biopsy）.Both cross-sectional and long-term follow-up trials have consistently associated OLGA stages Ⅲ-Ⅳ with a higher risk of GC.A recently-proposed modification of the OLGA staging system（OLGIM）basically incorporates the OLGA frame,but replaces the atrophy score with an assessment of intestinal metaplasia（IM）alone.A series of 4552 consecutive biopsy sets（2007-2009）was re-trieved and reassessed according to both the OLGA and the OLGIM staging systems.A set of at least 5 biopsy samples was available for all the cases considered.RESULTS：In 4460 of 4552 cases（98.0%）,both the high-risk stages（Ⅲ ＋ Ⅳ）and the low-risk stages（0 ＋Ⅰ ＋ Ⅱ）were assessed applying the OLGA and OL-GIM criteria.Among the 243 OLGA high-risk stages,14（5.8%）were down-staged to a low risk using OLGIM.The 67（1.5%）incidentally-found neoplastic lesions（intraepithelial or invasive）were consistently associated with high-risk stages,as assessed by both OLGA and OLGIM（P 〈 0.001 for both）.Two of 34 intestinal-type GCs coexisting with a high-risk OLGA stage（stage Ⅲ）were associated with a low-risk OLGIM stage（stage Ⅱ）.CONCLUSION：Gastritis staging systems（both OLGA and OLGIM）convey prognostically important informa-tion on the gastritis-associated cancer risk.Because of its clinical impact,the stage of gastritis should be included as a conclusive message in the gastritis histol-ogy report.Since it focuses on IM alone,OLGIM staging is less sensitive than OLGA staging in the identif ication of patients at high risk of gastric cancer.
Myeloid leukemias are a broad group of hematological disorders, characterized by heterogeneous clinical and biological features. In recent years, unprecedented genetic discoveries and ...clinical–biological correlations have revolutionized the field of myeloid leukemias. The most relevant changes have specifically occurred in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML) and myeloid neoplasms (MNs) with eosinophilia. The recently published International Consensus Classification (ICC) of myeloid neoplasms has addressed these changes, providing an updated framework and revised diagnostic criteria for such entities. This is also the aim of the 5th edition of the WHO classification of hematopoietic tumors, whose preliminary version was published in 2022. Parallel to this, new therapeutic options and novel molecular targets have changed the management of many myeloid entities, including AML and CML. This review aims to address the most relevant updates in the classification and diagnosis of AML, CMML, CML and MNs with eosinophilia. The state of the art of treatment and future therapeutic options for such disorders are also discussed.
Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive ...anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.
Mutations in neurofibromin, a Ras GTPase-activating protein, lead to the tumor predisposition syndrome neurofibromatosis type 1. Here, we report that cells lacking neurofibromin exhibit enhanced ...glycolysis and decreased respiration in a Ras/ERK-dependent way. In the mitochondrial matrix of neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1, a chaperone that promotes the accumulation of the oncometabolite succinate by inhibiting SDH. ERK1/2 enhances both formation of this multimeric complex and SDH inhibition. ERK1/2 kinase activity is favored by the interaction with TRAP1, and TRAP1 is, in turn, phosphorylated in an ERK1/2-dependent way. TRAP1 silencing or mutagenesis at the serine residues targeted by ERK1/2 abrogates tumorigenicity, a phenotype that is reverted by addition of a cell-permeable succinate analog. Our findings reveal that Ras/ERK signaling controls the metabolic changes orchestrated by TRAP1 that have a key role in tumor growth and are a promising target for anti-neoplastic strategies.
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•Cells lacking neurofibromin exhibit decreased respiration•ERK1/2 inhibits respiratory complex II (SDH) via phosphorylation of the chaperone TRAP1•SDH inhibition by ERK1/2 phosphorylation of TRAP1 is mandatory for neoplastic growth
Induction of the Ras/ERK signaling pathway characterizes many tumors and leads to metabolic changes whose oncogenic relevance is unclear. Masgras et al. reveal that ERK1/2 orchestrates a metabolic switch through phosphorylation of the mitochondrial chaperone TRAP1 and the ensuing inhibition of respiratory complex II that crucially contributes to neoplastic growth.
Interest in impedance-based cellular assays is rising due to their remarkable advantages, including label-free, low cost, non-invasive, non-destructive, quantitative and real-time monitoring. In ...order to test their potential in cancer treatment decision and early detection of chemoresistance, we devised a new custom-made impedance measuring system based on electric cell-substrate impedance sensing (ECIS), optimized for long term impedance measurements. This device was employed in a proof of concept cell culture impedance analysis for the characterization of chemo-resistant colon cancer cells. Doxorubicin-resistant HT-29 cells were used for this purpose and monitored for 140 h. Analysis of impedance-based curves reveal different trends from chemo-sensitive and chemo-resistant cells. An impedance-based cytoxicity assay with different concentrations of doxorubicin was also performed using ECIS. The obtained results confirm the feasibility of ECIS in the study of drug resistance and show promises for studies of time-dependent factors related to physiological and behavioral changes in cells during resistance acquisition. The methodology presented herein, allows the continuous monitoring of cells under normal culture conditions as well as upon drug exposure. The ECIS device used, sets the basis for high-throughput early detection of resistance to drugs, administered in the clinical practice to cancer patients, and for the screening of new drugs in vitro, on patient-derived cells.
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•Study of time-dependent factors related to drug resistance in colorectal cancer.•Impedance curves of drug-resistant cells differ from drug-sensitive ones.•Feasibility of impedance analysis in the study of chemoresistance.
Evaluation of B-cell clonality can be challenging in the interpretation of lymphoid infiltrates on tissue sections. Clonality testing based on IG gene rearrangements analysis by PCR (IG-PCR) is the ...gold standard. Alternatively, B-cell clonality can be assessed by the recognition of immunoglobulin light chain (IgLC) restriction, by immunohistochemistry (IHC), chromogenic in situ hybridization (ISH) or flow cytometry (FC). IG-PCR requires molecular facilities, and FC requires cell suspensions, both not widely available in routine pathology units. This study evaluates the performance of B-cell clonality detection by IgLC-RNAscope® (RNAsc) in a group of 216 formalin-fixed, paraffin-embedded samples including 185 non-Hodgkin B-cell lymphomas, 11 Hodgkin lymphomas (HL) and 20 reactive samples. IgLC-RNAsc, performed in parallel with FC in 53 cases, demonstrated better performances (93% vs 83%), particularly in diffuse large B-cell lymphoma (98% vs 71%) and follicular lymphoma (93% vs 83%) diagnosis. IgLC-RNAsc was also superior to IHC and ISH especially in samples with limited tumor cell content, where IG-PCR was not informative. Performed for the first time on mediastinal lymphomas, IgLC-RNAsc identified monotypic IgLC transcripts in 69% of primary mediastinal large B-cell lymphoma (PMBCL) and 67% of mediastinal gray zone lymphomas (MGZL). IGK/L double-negative cells were detected in 1 PMBCL, 2 MGZL, and all classical HL, while monotypic IgLC expression appeared to be a hallmark in nodular lymphocyte-predominant HL. IgLC-RNAsc demonstrates to be a powerful tool in B-cell lymphoma diagnosis, above all in challenging cases with limited tumor cell content, ensuring in situ investigations on mechanisms of Ig regulation across lymphoma entities.
Barrett's esophagus (BE) is characterized by the native stratified squamous epithelium (N) lining the esophagus being replaced by a columnar epithelium with intestinal differentiation (Barrett's ...mucosa; BM). BM is considered as the main risk factor for esophageal adenocarcinoma (Barrett's adenocarcinoma; BAc). MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting messenger RNAs and they are reportedly dysregulated in BM. To test the hypothesis that a specific miRNA expression signature characterizes BM development and progression, we performed miRNA microarray analysis comparing native esophageal mucosa with all the phenotypic lesions seen in the Barrett's carcinogenic process. Specimens were collected from 14 BE patients who had undergone esophagectomy, including: 14 with N, 14 with BM, 7 with low‐grade intraepithelial neoplasia, 5 with high‐grade intra‐epithelial neoplasia and 11 with BAc. Microarray findings were further validated by quantitive real‐time polymerase chain reaction and in situ hybridization analyses using a different series of consecutive cases (162 biopsy samples and 5 esophagectomies) of histologically proven, long‐segment BE. We identified a miRNA signature of Barrett's carcinogenesis consisting of an increased expression of 6 miRNAs and a reduced expression of 7 miRNAs. To further support these results, we investigated target gene expression using the Oncomine database and/or immunohistochemical analysis. We found that target gene expression correlated significantly with miRNA dysregulation. Specific miRNAs are directly involved in BE progression to cancer. miRNA profiling significantly expands current knowledge on the molecular history of Barrett's carcinogenesis, also identifying molecular markers of cancer progression.
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