Cell Reports
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.

Cancer biology & medicine, 2020
Authors
Chern, Yijye, Zhang, Peter, Ju, Hyelim, Tai, Isabella T
Publication Abstract
Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that facilitates collagen maturation. Its role in cancer remains largely unknown. In this study, we investigated the roles of HSP47 in colorectal cancer (CRC) and therapy resistance. Expression of HSP47 in CRC tissues was examined (1) in paired human CRC/adjacent normal tissues, using real time quantitative reverse transcription polymerase chain reaction (qRT-PCR), The Cancer Genome Atlas (TCGA) database, and 22 independent microarray databases (curated CRC). studies on several CRC cell lines (HCT116, RKO and CCL228) with modulated HSP47 expression were conducted to assess cell viability and apoptosis (TUNEL assay and caspase-3/-7) during exposure to chemotherapy. AKT signaling and co-immunoprecipitation studies were performed to examine HSP47 and PHLPP1 interaction. studies using tumor xenografts were conducted to assess the effects of HSP47 modulation on tumor growth and therapy response. HSP47 was upregulated in CRC and was associated with poor prognosis in individuals with CRC. , HSP47 overexpression supported the survival of CRC cells, whereas its knockdown sensitized cells to 5-fluorouracil (5-FU). HSP47 promoted survival by inhibiting apoptosis, enhancing AKT phosphorylation, and decreasing expression of the AKT-specific phosphatase PHLPP1 when cells were exposed to chemotherapy. These effects were partly results of the interaction between HSP47 and PHLPP1, which decreased PHLPP1 stability and led to more persistent AKT activity. , HSP47 supported tumor growth despite 5-FU treatment. HSP47 supports the growth of CRC tumors and suppresses the efficacy of chemotherapy modulation of AKT signaling.

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.

Expert opinion on drug discovery, 2020
Authors
Sadar, Marianne D
Publication Abstract

Intrinsically disordered proteins (IDPs) and regions (IDRs) lack stable three-dimensional structure making drug discovery challenging. A validated therapeutic target for diseases such as prostate cancer is the androgen receptor (AR) which has a disordered amino-terminal domain (NTD) that contains all of its transcriptional activity. Drug discovery against the AR-NTD is of intense interest as a potential treatment for disease such as advanced prostate cancer that is driven by truncated constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD).: This article presents an overview of the relevance of AR and its intrinsically disordered NTD as a drug target. AR structure and approaches to blocking AR transcriptional activity are discussed. The discovery of small molecules, including the libraries used, proven binders to the AR-NTD, and site of interaction of these small molecules in the AR-NTD are presented along with discussion of the Phase I clinical trial.: The lack of drugs in the clinic that directly bind IDPs/IDRs reflects the difficulty of targeting these proteins and obtaining specificity. However, it may also point to an inappropriateness of too closely borrowing concepts and resources from drug discovery to folded proteins.

Frontiers in Public Health
Authors
Nadine R Caron, Meck Chongo, Maui Hudson, Laura Arbour, Wyeth W Wasserman, Stephen Robertson, Solenne Correard, Phillip Wilcox
Publication Abstract

The potential to grow genomic knowledge and harness the subsequent clinical benefits has escalated the building of background variant databases (BVDs) for genetic diagnosis across the globe. Alongside the upsurge of this precision medicine, potential benefits have been highlighted for both rare genetic conditions and other diagnoses. However, with the ever-present “genomic divide,” Indigenous peoples globally have valid concerns as they endure comparatively greater health disparities but stand to benefit the least from these novel scientific discoveries and progress in healthcare. The paucity of Indigenous healthcare providers and researchers in these fields contributes to this genomic divide both in access to, and availability of culturally safe, relevant and respectful healthcare using this genetic knowledge. The vital quest to provide equitable clinical research, and provision and use of genomic services and technologies provides a strong rationale for building BVDs for Indigenous peoples. Such tools would ground their representation and participation in accompanying genomic health research and benefit acquisition. We describe two, independent but highly similar initiatives–the “Silent Genomes” in Canada and the “Aotearoa Variome” in New Zealand–as exemplars that have had to address the aforementioned issues and work to create Indigenous BVDs with these populations. Taking into account the baseline inequities in genomic medicine for Indigenous populations and the ongoing challenges of implementing genomic research with Indigenous communities, we provide a rationale for multiple changes required that will assure communities represented in BVDs, as well as Indigenous researchers, that their participation will maximize benefits and minimize risk.

Neuro-Oncology
Authors
Alexandra K Bohm, Jessica DePetro, Carmen E Binding, Amanda Gerber, Nicholas Chahley, N Dan Berger, Mathaeus Ware, Kaitlin Thomas, U Senapathi, Shazreh Bukhari, Cindy Chen, Erin Chahley, Cameron Grisdale, Sam Lawn, Yaping Yu, Raymond Wong, Yaoqing Shen, Hiba Omairi, Reza Mirzaei, Nourah Alshatti, Haley Pedersen, Wee Yong, Samuel Weiss, Jennifer Chan, P J Cimino, John Kelly, Steve Jones, Eric Holland, Michael Blough, Gregory Cairncross
Publication Abstract

Background

Imagining ways to prevent or treat glioblastoma (GBM) has been hindered by a lack of understanding of its pathogenesis. Although overexpression of platelet derived growth factor with two A-chains (PDGF-AA) may be an early event, critical details of the core biology of GBM are lacking. For example, existing PDGF-driven models replicate its microscopic appearance, but not its genomic architecture. Here we report a model that overcomes this barrier to authenticity.

Methods

Using a method developed to establish neural stem cell cultures, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, one of the putative cells of origin of GBM. We microdissected SVZ tissue from p53-null and wild-type adult mice, cultured cells in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumorigenicity.

Results

Counterintuitive to its canonical role as a growth factor, we observed abrupt and massive cell death in PDGF-AA: wild-type cells did not survive, whereas a small fraction of null cells evaded apoptosis. Surviving null cells displayed attenuated proliferation accompanied by whole chromosome gains and losses. After approximately 100 days in PDGF-AA, cells suddenly proliferated rapidly, acquired growth factor independence, and became tumorigenic in immune-competent mice. Transformed cells had an oligodendrocyte precursor-like lineage marker profile, were resistant to platelet derived growth factor receptor alpha inhibition, and harbored highly abnormal karyotypes similar to human GBM.

Conclusion

This model associates genome instability in neural progenitor cells with chronic exposure to PDGF-AA and is the first to approximate the genomic landscape of human GBM and the first in which the earliest phases of the disease can be studied directly.

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.

Blood, 2020
Authors
Hanyang Lin, Katharina Rothe, Min Chen, Andrew Wu, Artem Babaian, Ryan Yen, Jonathan Zeng, Jens Ruschmann, Oleh I Petriv, Kieran O'Neill, Tobias Maetzig, David J H F Knapp, Naoto Nakamichi, Ryan Brinkman, Inanc Birol, Donna L Forrest, Carl Hansen, Keith Keith Humphries, Connie J Eaves, Xiaoyan Jiang
Publication Abstract

Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of miRNAs in regulating drug resistance and leukemic stem cell (LSCs) fate, we performed global transcriptome profiling in treatment-naïve chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor; its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in pre-clinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185 and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in patients.

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