Cell Reports, 2020
Authors
Artem Babaian, Katharina Rothe, Dylan Girodat, Igor Minia, Sara Djondovic, Miha Milek, Sandra E Spencer Miko, Hans-Joachim Wieden, Markus Landthaler, Gregg B Morin, Dixie L Mager
Publication Abstract

The ribosome is an RNA-protein complex that is essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) genes are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We identify a cancer-specific single-nucleotide variation in 18S rRNA at nucleotide 1248.U in up to 45.9% of patients with colorectal carcinoma (CRC) and present across >22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3-α-amino-α-carboxyl-propyl pseudouridine (m1acp3Ψ), a >1-billion-years-conserved RNA modification at the peptidyl decoding site of the ribosome. A subset of CRC tumors we call hypo-m1acp3Ψ shows sub-stoichiometric m1acp3Ψ modification, unlike normal control tissues. An m1acp3Ψ knockout model and hypo-m1acp3Ψ patient tumors share a translational signature characterized by highly abundant ribosomal proteins. Thus, m1acp3Ψ-deficient rRNA forms an uncharacterized class of “onco-ribosome” which may serve as a chemotherapeutic target for treating cancer patients.

Blood, 2020
Authors
Luca Malcovati, Kristen Stevenson, Elli Papaemmanuil, Donna Neuberg, Rafael Bejar, Jacqueline Boultwood, David T Bowen, Peter J Campbell, Benjamin L Ebert, Pierre Fenaux, Torsten Haferlach, Michael Heuser, Joop H Jansen, Rami S Komrokji, Jaroslaw P Maciejewski, Matthew J Walter, Michaela Fontenay, Guillermo Garcia-Manero, Timothy A Graubert, Aly Karsan, Manja Meggendorfer, Andrea Pellagatti, David A Sallman, Michael R Savona, Mikkael Sekeres, David P Steensma, Sudhir Tauro, Felicitas Thol, Paresh Vyas, Arjan A Van de Loosdrecht, Detlef Thomas Haase, Heinz Tuechler, Peter L Greenberg, Seishi Ogawa, Eva S Hellstrom-Lindberg, Mario Cazzola.
Publication Abstract

The 2016 revision of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues is characterized by a closer integration of morphology and molecular genetics. Notwithstanding, the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality. About half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one. SF3B1 mutation identifies a condition characterized by ring sideroblasts, ineffective erythropoiesis, and indolent clinical course. A large body of evidence supports recognition of SF3B1-mutant MDS as a distinct nosologic entity. To further validate this notion, we interrogated the dataset of the International Working Group for the Prognosis of MDS (IWG-PM). Based on the findings of our analyses, we propose the following diagnostic criteria for SF3B1-mutant MDS: (i) cytopenia as defined by standard hematologic values; (ii) somatic SF3B1 mutation; (iii) morphologic dysplasia (with or without ring sideroblasts); (iv) bone marrow blasts <5% and peripheral blood blasts <1%. Selected concomitant genetic lesions represent exclusion criteria for the proposed entity. In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overt MDS with ring sideroblasts, suggesting that this genetic lesion provides presumptive evidence of MDS in the setting of persistent unexplained cytopenia. Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making. In fact, this condition has a relatively good prognosis and may respond to luspatercept with abolishment of transfusion requirement.

Human Pathology
Authors
Basile Tessier-Cloutier, Dawn R Cochrane, Anthony N Karnezis, Shane Colborne, Jamie Magrill, Aline Talhouk, Jonathan Zhang, Samuel Leung, Christopher S Hughes, Anna Piskorz, Angela S Cheng, Kendall Greening, Andreas du Bois, Jacobus Pfisterer, Robert A Soslow, Stefan Kommoss, James D Brenton, Gregg B Morin, C Blake Gilks, David G Huntsman, Friedrich Kommoss.
Publication Abstract

The current WHO classification does not separate transitional cell-like carcinoma of the ovary (TCC) from conventional tubo-ovarian high-grade serous carcinoma (HGSC), despite evidence suggesting improved prognosis for patients with TCC; it is considered, instead a morphologic variant of HGSC. The immunohistochemical (IHC) markers applied to date do not distinguish between TCC and HGSC. Therefore, we sought to compare the proteomic profiles of TCC and conventional HGSC to identify proteins enriched in TCC. Prognostic biomarkers in HGSC have proven elusive and our aim was to identify biomarkers of TCC as a way of reliably and reproducibly identifying patients with a favorable prognosis and better response to chemotherapy compared to those with conventional HGSC. Quantitative global proteome analysis was performed on archival material of 12 cases of TCC and 16 cases of HGSC using SP3-CTP, a recently described protocol for full proteome analysis from formalin-fixed paraffin-embedded tissues. We identified 430 proteins that were significantly enriched in TCC over HGSC. Unsupervised co-clustering perfectly separated TCC from HGSC based on protein expression. Pathway analysis showed that proteins associated with cell death, necrosis and apoptosis were highly expressed in TCCs, while DNA homologous recombination, cell mitosis, proliferation and survival and cell cycle progression pathways had reduced expression. From the proteomic analysis, three potential biomarkers for TCC were identified, claudin-4 (CLDN4), ubiquitin carboxyl-terminal esterase L1 (UCHL1) and minichromosome maintenance protein 7 (MCM7) and tested by IHC on tissue microarrays. In agreement with the proteomic analysis, IHC expression for those proteins was stronger in TCC compared to HGSC (p<0.0001). Using global proteomic analysis, we are able to separate TCC from conventional HGSC. Follow up studies will be necessary to confirm that these molecular and morphologic differences are clinically significant.

Nucleic Acids Research, 2020
Authors
Nawar Malhis, Matthew Jacobson, Steven J M Jones, Jörg Gsponer
Publication Abstract

The separation of deleterious from benign mutations remains a key challenge in the interpretation of genomic data. Computational methods used to sort mutations based on their potential deleteriousness rely largely on conservation measures derived from sequence alignments. Here, we introduce LIST-S2, a successor to our previously developed approach LIST, which aims to exploit local sequence identity and taxonomy distances in quantifying the conservation of human protein sequences. Unlike its predecessor, LIST-S2 is not limited to human sequences but can assess conservation and make predictions for sequences from any organism. Moreover, we provide a web-tool and downloadable software to compute and visualize the deleteriousness of mutations in user-provided sequences. This web-tool contains an HTML interface and a RESTful API to submit and manage sequences as well as a browsable set of precomputed predictions for a large number of UniProtKB protein sequences of common taxa. LIST-S2 is available at: https://list-s2.msl.ubc.ca/

Journal of Proteome Research, 2020
Authors
Jianhui Cheng, Lingyu Wang, Craig M Rive, Robert A Holt, Gregg B Morin, David D Y Chen
Publication Abstract

Mass spectrometry is a powerful tool for de novo sequencing of novel proteins. Recent efforts in this area have mainly focused on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Here, we present an alternative method, capillary electrophoresis tandem mass spectrometry (CE-MS/MS), for sequencing novel monoclonal antibodies. Using less than 200 ng in total of tryptic digest sample in a triplicated measurement, CE-MS/MS with pH-mediated focusing successfully sequenced mAb infliximab with 100% sequence coverage and 100% accuracy for the light chain and 96% coverage and 93% accuracy for the heavy chain. It was also demonstrated that CE-MS/MS gives comparable results, and in some cases, even better results, as compared to LC-MS/MS when used as a standalone technique. A combined workflow using both CE-MS/MS and LC-MS/MS was also used to sequence a novel antibody, anti-CD-176, resulting in the first proposed sequence for this mAb.

Nature Methods, 2020
Authors
Ottar N Bjørnstad, Katriona Shea, Martin Krzywinski, Naomi Altman.
Publication Abstract

In the next few articles, we will discuss mathematical and statistical models that are commonly used to study the spread of infectious diseases. Such models are used to inform decisions on disease prevention, surveillance, control and treatment and can be applied to new epidemics, such as the ongoing COVID-19 outbreak.

Nature cell biology, 2020
Authors
Martinez-Høyer, Sergio, Deng, Yu, Parker, Jeremy, Jiang, Jihong, Mo, Angela, Docking, T Roderick, Gharaee, Nadia, Li, Jenny, Umlandt, Patricia, Fuller, Megan, Jädersten, Martin, Kulasekararaj, Austin, Malcovati, Luca, List, Alan F, Hellström-Lindberg, Eva, Platzbecker, Uwe, Karsan, Aly
Publication Abstract
Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the most common structural genomic variant in myelodysplastic syndromes (MDS){{sup}}1{{/sup}}. Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant{{sup}}2{{/sup}} within 2 years. TP53 mutations are detected in ~20% of LEN-resistant patients{{sup}}3{{/sup}}. Here we show that patients who become resistant to LEN harbour recurrent variants of TP53 or RUNX1. LEN upregulated RUNX1 protein and function in a CRBN- and TP53-dependent manner in del(5q) cells, and mutation or downregulation of RUNX1 rendered cells resistant to LEN. LEN induced megakaryocytic differentiation of del(5q) cells followed by cell death that was dependent on calpain activation and CSNK1A1 degradation{{sup}}4,5{{/sup}}. We also identified GATA2 as a LEN-responsive gene that is required for LEN-induced megakaryocyte differentiation. Megakaryocytic gene-promoter analyses suggested that LEN-induced degradation of IKZF1 enables a RUNX1-GATA2 complex to drive megakaryocytic differentiation. Overexpression of GATA2 restored LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for mutations that block LEN-induced megakaryocytic differentiation should identify patients who are resistant to LEN.

The journals of gerontology. Series A, Biological sciences and medical sciences, 2020
Authors
Tindale, Lauren C, Thiessen, Nina, Leach, Stephen, Brooks-Wilson, Angela R
Publication Abstract
The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

Cancer Cell
Authors
George W Wright, Da Wei Huang, James D Phelan, Zana A Coulibaly, Sandrine Roulland, Ryan M Young, James Q Wang, Roland Schmitz, Ryan D Morin, Jeffrey Tang, Aixiang Jiang, Aleksander Bagaev, Olga Plotnikova, Nikita Kotlov, Calvin A Johnson, Wyndham H Wilson, David W Scott, Louis M Staudt
Publication Abstract

The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials.

Organic Letters
Authors
Kalindi D Morgan, David E Williams, Brian O Patrick, Marion Remigy, Carmen A Banuelos, Marianne D Sadar, Katherine S Ryan, Raymond J Andersen
Publication Abstract

Methods for the focused isolation of low-abundance natural products with specific chemical substructures could expand known bioactive chemical diversity for drug discovery. Here we report the combined use of genome mining and an 15N NMR-based screening method for the targeted isolation of the low-abundance piperazic-acid-containing peptides incarnatapeptins A (1) and B (3). Incarnatapeptin B (3) shows in vitro cytotoxicity to LNCaP prostate cancer cells.

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