Genetic Phenomena Commons^™

Landscape Of Notch1 Mutations And Co-Occurring Biomarker Alterations In Chronic Lymphocytic Leukemia, Fatima Zahra Jelloul, Richard Yang, Sofia Garces, Rashmi Kanagal-Shamanna, Chi Y Ok, Sanam Loghavi, Mark J Routbort, Zhuang Zuo, C Cameron Yin, Kristen Floyd, Roland L Bassett, William Wierda, Nitin Jain, Philip Thompson, Rajyalakshmi Luthra, L Jeffrey Medeiros, Keyur P Patel

Faculty, Staff and Student Publications

NOTCH1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and has emerged as a marker of poor prognosis. In addition to coding NOTCH1 mutations involving exon 34, non-coding NOTCH1 mutations involving the 3' UTR have been described in a limited number of chronic lymphocytic leukemia (CLL) patients and were associated with adverse outcomes. In this study, 1574 CLL patients were assessed using targeted sequencing with a 29 gene panel and the results were correlated with prognostic characteristics. NOTCH1 mutations were detected in 252 (16%) patients, including both coding (220/252, 14%), non-coding (24/252, 1.5%) and a mixture …

Barriers And Facilitators Of Implementing Automated Radiotherapy Planning: A Multisite Survey Of Low- And Middle-Income Country Radiation Oncology Providers, Gwendolyn J Mcginnis, Matthew S Ning, Beth M Beadle, Nanette Joubert, William Shaw, Christoph Trauernich, Hannah Simonds, Surbhi Grover, Carlos E Cardenas, Laurence E Court, Grace L Smith

Faculty, Staff and Student Publications

Purpose: Global access to radiotherapy (RT) is inequitable, with obstacles to implementing modern technologies in low- and middle- income countries (LMICs). The Radiation Planning Assistant (RPA) is a web-based automated RT planning software package intended to increase accessibility of high-quality RT planning. We surveyed LMIC RT providers to identify barriers and facilitators of future RPA deployment and uptake.

Methods: RT providers underwent a pilot RPA teaching session in sub-Saharan Africa (Botswana, South Africa, and Tanzania) and Central America (Guatemala). Thirty providers (30 of 33, 90.9% response rate) participated in a postsession survey.

Results: Respondents included physicians (n = 10, 33%), …

Activity Of Decitabine As Maintenance Therapy In Core Binding Factor Acute Myeloid Leukemia, Jayastu Senapati, Mahran Shoukier, Guillermo Garcia-Manero, Xuemei Wang, Keyur Patel, Tapan Kadia, Farhad Ravandi, Naveen Pemmaraju, Maro Ohanian, Naval Daver, Courtney Dinardo, Yesid Alvarado, Jeffrey Aldrich, Gautam Borthakur

Faculty, Staff and Student Publications

Background: Posttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML.

Methods: We prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%.

Results: Thirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received …

Home Cooking Quality Assessment Tool Validation Using Community Science And Crowdsourcing Approaches, Margaret Raber, Nalini Ranjit, Larkin L Strong, Karen Basen-Engquist

Faculty, Staff and Student Publications

Objective: To refine a measure of home cooking quality (defined as the usage level of practices with the potential to influence the nutrient content of prepared foods) and conduct a construct validation of the revised tool, the Healthy Cooking Questionnaire 2 (HCQ2).

Design: Two validation approaches are described: (1) a community science approach used to refine and validate Healthy Cooking Questionnaire (HCQ) constructs, and (2) responses to the revised HCQ (HCQ2) in a sample of Amazon Mechanical Turk (MTurk) workers to determine questionnaire comprehension.

Setting: The Community Scientist Program at the University of Texas MD Anderson Cancer Center facilitated discussion …

Ovarian Cancer Reporting Lexicon For Computed Tomography (Ct) And Magnetic Resonance (Mr) Imaging Developed By The Sar Uterine And Ovarian Cancer Disease-Focused Panel And The Esur Female Pelvic Imaging Working Group, Atul B Shinagare, Elizabeth A Sadowski, Hyesun Park, Olga R Brook, Rosemarie Forstner, Sumer K Wallace, Jeanne M Horowitz, Neil Horowitz, Marcia Javitt, Priyanka Jha, Aki Kido, Yulia Lakhman, Susanna I Lee, Lucia Manganaro, Katherine E Maturen, Stephanie Nougaret, Liina Poder, Gaiane M Rauch, Caroline Reinhold, Evis Sala, Isabelle Thomassin-Naggara, Herbert Alberto Vargas, Aradhana Venkatesan, Olivera Nikolic, Andrea G Rockall

Faculty, Staff and Student Publications

Objectives: Imaging evaluation is an essential part of treatment planning for patients with ovarian cancer. Variation in the terminology used for describing ovarian cancer on computed tomography (CT) and magnetic resonance (MR) imaging can lead to ambiguity and inconsistency in clinical radiology reports. The aim of this collaborative project between Society of Abdominal Radiology (SAR) Uterine and Ovarian Cancer (UOC) Disease-focused Panel (DFP) and the European Society of Uroradiology (ESUR) Female Pelvic Imaging (FPI) Working Group was to develop an ovarian cancer reporting lexicon for CT and MR imaging.

Methods: Twenty-one members of the SAR UOC DFP and ESUR FPI …

Definitive Radiotherapy For Extracranial Oligoprogressive Metastatic Renal Cell Carcinoma As A Strategy To Defer Systemic Therapy Escalation, Brian De, Aradhana M Venkatesan, Pavlos Msaouel, Amol J Ghia, Jing Li, Debra N Yeboa, Quynh-Nhu Nguyen, Andrew J Bishop, Eric Jonasch, Amishi Y Shah, Matthew T Campbell, Jennifer Wang, Amado J Zurita-Saavedra, Jose A Karam, Christopher G Wood, Surena F Matin, Nizar M Tannir, Chad Tang

Faculty, Staff and Student Publications

Objective: To study whether delivering definitive radiotherapy (RT) to sites of oligoprogression in metastatic renal cell carcinoma (mRCC) enabled deferral of systemic therapy (ST) changes without compromising disease control or survival.

Patients and methods: We identified patients with mRCC who received RT to three or fewer sites of extracranial progressive disease between 2014 and 2019 at a large tertiary cancer centre. Inclusion criteria were: (1) controlled disease for ≥3 months before oligoprogression, (2) all oligoprogression sites treated with a biologically effective dose of ≥100 Gy, and (3) availability of follow-up imaging. Time-to-event end-points were calculated from the start of RT. …

Home Cooking Quality Assessment Tool Validation Using Community Science And Crowdsourcing Approaches, Margaret Raber, Nalini Ranjit, Larkin L Strong, Karen Basen-Engquist

Faculty, Staff and Student Publications

Objective: To refine a measure of home cooking quality (defined as the usage level of practices with the potential to influence the nutrient content of prepared foods) and conduct a construct validation of the revised tool, the Healthy Cooking Questionnaire 2 (HCQ2).

Design: Two validation approaches are described: (1) a community science approach used to refine and validate Healthy Cooking Questionnaire (HCQ) constructs, and (2) responses to the revised HCQ (HCQ2) in a sample of Amazon Mechanical Turk (MTurk) workers to determine questionnaire comprehension.

Setting: The Community Scientist Program at the University of Texas MD Anderson Cancer Center facilitated discussion …

Dance Of The Golgi: Understanding Golgi Dynamics In Cancer Metastasis, Rakhee Bajaj, Amanda N Warner, Jared F Fradette, Don L Gibbons

Faculty, Staff and Student Publications

The Golgi apparatus is at the center of protein processing and trafficking in normal cells. Under pathological conditions, such as in cancer, aberrant Golgi dynamics alter the tumor microenvironment and the immune landscape, which enhances the invasive and metastatic potential of cancer cells. Among these changes in the Golgi in cancer include altered Golgi orientation and morphology that contribute to atypical Golgi function in protein trafficking, post-translational modification, and exocytosis. Golgi-associated gene mutations are ubiquitous across most cancers and are responsible for modifying Golgi function to become pro-metastatic. The pharmacological targeting of the Golgi or its associated genes has been …

Accessory Genomes Drive Independent Spread Of Carbapenem-Resistant Klebsiella Pneumoniae Clonal Groups 258 And 307 In Houston, Tx, William C Shropshire, An Q Dinh, Michelle Earley, Lauren Komarow, Diana Panesso, Kirsten Rydell, Sara I Gómez-Villegas, Hongyu Miao, Carol Hill, Liang Chen, Robin Patel, Bettina C Fries, Lilian Abbo, Eric Cober, Sara Revolinski, Courtney L Luterbach, Henry Chambers, Vance G Fowler, Robert A Bonomo, Samuel A Shelburne, Barry N Kreiswirth, David Van Duin, Blake M Hanson, Cesar A Arias

Faculty, Staff and Student Publications

Carbapenem-resistant Klebsiella pneumoniae (CRKp) is an urgent public health threat. Worldwide dissemination of CRKp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CRKp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 …

Reduction Of Mutant Atxn1 Rescues Premature Death In A Conditional Sca1 Mouse Model, James P Orengo, Larissa Nitschke, Meike E Van Der Heijden, Nicholas A Ciaburri, Harry T Orr, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses, motor neurons are affected, and their dysfunction contributes toward the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1, we created a conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model; however, they took twice as long to develop. We found that …

Clinical Diagnosis Of Metabolic Disorders Using Untargeted Metabolomic Profiling And Disease-Specific Networks Learned From Profiling Data, Lillian R Thistlethwaite, Xiqi Li, Lindsay C Burrage, Kevin Riehle, Joseph G Hacia, Nancy Braverman, Michael F Wangler, Marcus J Miller, Sarah H Elsea, Aleksandar Milosavljevic

Duncan NRI Faculty and Staff Publications

Untargeted metabolomics is a global molecular profiling technology that can be used to screen for inborn errors of metabolism (IEMs). Metabolite perturbations are evaluated based on current knowledge of specific metabolic pathway deficiencies, a manual diagnostic process that is qualitative, has limited scalability, and is not equipped to learn from accumulating clinical data. Our purpose was to improve upon manual diagnosis of IEMs in the clinic by developing novel computational methods for analyzing untargeted metabolomics data. We employed CTD, an automated computational diagnostic method that "connects the dots" between metabolite perturbations observed in individual metabolomics profiling data and modules identified …

Venetoclax Combinations Delay The Time To Deterioration Of Hrqol In Unfit Patients With Acute Myeloid Leukemia, Keith W Pratz, Panayiotis Panayiotidis, Christian Recher, Xudong Wei, Brian A Jonas, Pau Montesinos, Vladimir Ivanov, Andre C Schuh, Courtney D Dinardo, Jan Novak, Vlatko Pejsa, Don Stevens, Su-Peng Yeh, Inho Kim, Mehmet Turgut, Nicola Fracchiolla, Kazuhito Yamamoto, Yishai Ofran, Andrew H Wei, Cat N Bui, Katy Benjamin, Rajesh Kamalakar, Jalaja Potluri, Wellington Mendes, Jacob Devine, Walter Fiedler

Faculty, Staff and Student Publications

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups …

Convection Enhanced Delivery Of The Oncolytic Adenovirus Delta24-Rgd In Patients With Recurrent Gbm: A Phase I Clinical Trial Including Correlative Studies, Erik H P Van Putten, Anne Kleijn, Victor W Van Beusechem, David Noske, Cor H J Lamers, Anna L De Goede, Sander Idema, Daphna Hoefnagel, Jenneke J Kloezeman, Juan Fueyo, Frederick F Lang, Charlotte E Teunissen, René M Vernhout, Cathy Bakker, Winald Gerritsen, David T Curiel, Arnold Vulto, Martine L M Lamfers, Clemens M F Dirven

Faculty, Staff and Student Publications

Purpose: Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.

Patients and methods: Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.

Results: Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. …

Distinct Molecular And Immune Hallmarks Of Inflammatory Arthritis Induced By Immune Checkpoint Inhibitors For Cancer Therapy, Sang T Kim, Yanshuo Chu, Mercy Misoi, Maria E Suarez-Almazor, Jean H Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S Neelapu, Jennifer Wang, Amishi Y Shah, Nizar M Tannir, Matthew T Campbell, Don L Gibbons, Tina Cascone, Charles Lu, George R Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E Loghin, Janet Tu, Shannon N Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A Tawbi, Patrick Hwu, Isabella C Glitza Oliva, Michael A Davies, Sapna P Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8

Autologous Stem Cell Transplantation For Large B-Cell Lymphoma With Secondary Central Nervous System Involvement, Serkan Akin, Chitra Hosing, Issa Khouri, Sairah Ahmed, Amin Alousi, Nathan Fowler, Jacinth Joseph, Jonathan Truxillo, Jeremy L Ramdial, Farzaneh Maadani, Gabriela Rondon, May Daher, Jin S Im, Raphael Steiner, Jason Westin, Swaminathan P Iyer, Bouthaina Dabaja, Paolo Anderlini, Uday R Popat, Muzaffar H Qazilbash, Christopher R Flowers, Elizabeth Shpall, Richard E Champlin, Yago Nieto, Samer A Srour

Faculty, Staff and Student Publications

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare, with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression-free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 …

Ndrg1 In Aggressive Breast Cancer Progression And Brain Metastasis, Emilly S Villodre, Xiaoding Hu, Bedrich L Eckhardt, Richard Larson, Lei Huo, Ester C Yoon, Yun Gong, Juhee Song, Shuying Liu, Naoto T Ueno, Savitri Krishnamurthy, Stefan Pusch, Debu Tripathy, Wendy A Woodward, Bisrat G Debeb

Faculty, Staff and Student Publications

BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.

METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test …

Meta-Analysis Of Genome-Wide Association Studies Identifies Ancestry-Specific Associations Underlying Circulating Total Tau Levels, Chloé Sarnowski, Mohsen Ghanbari, Joshua C Bis, Mark Logue, Myriam Fornage, Aniket Mishra, Shahzad Ahmad, Alexa S Beiser, Eric Boerwinkle, Vincent Bouteloup, Vincent Chouraki, L Adrienne Cupples, Vincent Damotte, Charles S Decarli, Anita L Destefano, Luc Djoussé, Alison E Fohner, Carol E Franz, Tiffany F Kautz, Jean-Charles Lambert, Michael J Lyons, Thomas H Mosley, Kenneth J Mukamal, Matthew P Pase, Eliana C Portilla Fernandez, Robert A Rissman, Claudia L Satizabal, Ramachandran S Vasan, Amber Yaqub, Stephanie Debette, Carole Dufouil, Lenore J Launer, William S Kremen, William T Longstreth, M Arfan Ikram, Sudha Seshadri

Faculty, Staff and Student Publications

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

Exploiting 4–1bb Immune Checkpoint To Enhance The Efficacy Of Oncolytic Virotherapy For Diffuse Intrinsic Pontine Gliomas, Virginia Laspidea, Montserrat Puigdelloses, Sara Labiano, Lucía Marrodán, Marc Garcia-Moure, Marta Zalacain, Marisol Gonzalez-Huarriz, Naiara Martínez-Vélez, Iker Ausejo-Mauleon, Daniel De La Nava, Guillermo Herrador-Cañete, Javier Marco-Sanz, Elisabeth Guruceaga, Carlos E De Andrea, María Villalba, Oren Becher, Massimo Squatrito, Verónica Matía, Jaime Gállego Pérez-Larraya, Ana Patiño-García, Sumit Gupta, Candelaria Gomez-Manzano, Juan Fueyo, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed …

Loss-Of-Function Variants In Tiam1 Are Associated With Developmental Delay, Intellectual Disability, And Seizures, Shenzhao Lu, Rebecca Hernan, Paul C Marcogliese, Yan Huang, Tracy S Gertler, Meltem Akcaboy, Shiyong Liu, Hyung-Lok Chung, Xueyang Pan, Xiaoqin Sun, Melahat Melek Oguz, Ulkühan Oztoprak, Jeroen H F De Baaij, Jelena Ivanisevic, Erin Mcginnis, Maria J Guillen Sacoto, Wendy K Chung, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in …

Hsp90-Cdc37 Functions As A Chaperone For The Oncogenic Fgfr3-Tacc3 Fusion, Tao Li, Farideh Mehraein-Ghomi, M Elizabeth Forbes, Sanjeev V Namjoshi, E Ashley Ballard, Qianqian Song, Ping-Chieh Chou, Xuya Wang, Brittany C Parker Kerrigan, Frederick F Lang, Glenn Lesser, Waldemar Debinski, Xuejun Yang, Wei Zhang

Faculty, Staff and Student Publications

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated …

Disrupting The Myc-Tfeb Circuit Impairs Amino Acid Homeostasis And Provokes Metabolic Anergy, Mario R Fernandez, Franz X Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K Schaub, Frank C Dorsey, Min Liu, Meredith A Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M Koomen, Anders E Berglund, John L Cleveland

Duncan NRI Faculty and Staff Publications

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA …

Standardisation Of Protocols Can Be Crucial In Long Non-Coding Rna Research, Kinga Németh, George A Calin

Faculty, Staff and Student Publications

In this issue, Traversa et al. [1] reviewed our current knowledge about the role of circular and linear forms of PVT1 non-coding RNA in cancer and human diseases. They highlighted the technical challenges of these studies and raised a potential bias in the publications, which require more attention from researchers.

Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable With Isolated Isochromosome 17q Represents A Distinct Clinico-Biologic Subset: A Multi-Institutional Collaborative Study From The Bone Marrow Pathology Group, Rashmi Kanagal-Shamanna, Attilio Orazi, Robert P Hasserjian, Daniel A Arber, Kaaren Reichard, Eric D Hsi, Adam Bagg, Heesun Joyce Rogers, Julia Geyer, Faezeh Darbaniyan, Kim-Anh Do, Kyle M Devins, Olga Pozdnyakova, Tracy I George, Paola Dal Cin, Patricia T Greipp, Mark J Routbort, Keyur Patel, Guillermo Garcia-Manero, Srdan Verstovsek, L Jeffrey Medeiros, Sa A Wang, Carlos Bueso-Ramos

Faculty, Staff and Student Publications

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated …

Pgc1Α/Β Expression Predicts Therapeutic Response To Oxidative Phosphorylation Inhibition In Ovarian Cancer, Carmen Ghilardi, Catarina Moreira-Barbosa, Laura Brunelli, Paola Ostano, Nicolò Panini, Monica Lupi, Alessia Anastasia, Fabio Fiordaliso, Monica Salio, Laura Formenti, Massimo Russo, Edoardo Arrigoni, Ferdinando Chiaradonna, Giovanna Chiorino, Giulio Draetta, Joseph R Marszalek, Christopher P Vellano, Roberta Pastorelli, Mariarosa Bani, Alessandra Decio, Raffaella Giavazzi

Faculty, Staff and Student Publications

Ovarian cancer is the deadliest gynecologic cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control ovarian cancer progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC1α and PGC1β. In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1α and PGC1β (PGC1α/β) fostered a unique transcriptional signature, leading to increased mitochondrial abundance, enhanced tricarboxylic acid cycling, and elevated cellular respiration that ultimately conferred vulnerability to OXPHOS inhibition. Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling …

Camk2/Camkii Activates Mlkl In Short-Term Starvation To Facilitate Autophagic Flux, Qionghui Zhan, Jaepyo Jeon, Ying Li, Yu Huang, Jian Xiong, Qiaochu Wang, Tian-Le Xu, Yong Li, Fu-Hai Ji, Guangwei Du, Michael X Zhu

Faculty, Staff and Student Publications

MLKL (mixed lineage kinase domain like pseudokinase) is a well-known core component of necrosome that executes necroptotic cell death upon phosphorylation by RIPK3 (receptor interacting serine/threonine kinase 3). Recent studies also implicate a role of MLKL in endosomal trafficking, which is not always dependent on RIPK3. Using mouse Neuro-2a and L929 as well as human HEK293 and HT29 cells, we show here that MLKL is phosphorylated in response to serum and amino acid deprivation from the culture medium, in a manner that depends on CAMK2/CaMKII (calcium/calmodulin dependent protein kinase II) but not RIPK3. The starvation-induced increase in MLKL phosphorylation was …

The Paradox Of Immunosuppressants And Covid-19, Guang-Shing Cheng, Scott E Evans

Faculty, Staff and Student Publications

Lessons learned from a large registry analysis show worse COVID-19 outcomes for patients previously exposed to glucocorticoids https://bit.ly/306rNrk

Citation Analysis Of The Most Influential Ependymoma Research Articles Illustrates Improved Knowledge Of The Molecular Biology Of Ependymoma, Nolan J Brown, Bayard Wilson, Brian V Lien, Alexander Himstead, Ali R Tafreshi, Shane Shahrestani, Jack Birkenbeuel, Katelynn Tran, David Horton, Anushka Paladugu, Lydia R Kirillova, Chen Yi Yang, Seth C Ransom, Ronald Sahyouni, Isaac Yang

Faculty, Staff and Student Publications

The history of academic research on ependymoma is expansive. This review summarizes its history with a bibliometric analysis of the 100 most cited articles on ependymoma. In March 2020, we queried the Web of Science database to identify the most cited articles on ependymoma using the terms "ependymoma" or "ependymal tumors," yielding 3145 publications. Results were arranged by the number of times each article was cited in descending order. The top 100 articles spanned across nearly a century; the oldest article was published in 1924, while the most recent was in 2017. These articles were published in 35 unique journals, …

Predictive Radiation Oncology - A New Nci-Doe Scientific Space And Community, Jeffrey C Buchsbaum, David A Jaffray, Demba Ba, Lynn L Borkon, Christine Chalk, Caroline Chung, Matthew A Coleman, C Norman Coleman, Maximilian Diehn, Kelvin K Droegemeier, Heiko Enderling, Michael G Espey, Emily J Greenspan, Christopher M Hartshorn, Thuc Hoang, H Timothy Hsiao, Cynthia Keppel, Nathan W Moore, Fred Prior, Eric A Stahlberg, Georgia Tourassi, Karen E Willcox

Faculty, Staff and Student Publications

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops-and a final concluding "World Café" on March 29, 2021-focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, …

Enzymatic Characterization Of Mrna Cap Adenosine-N6 Methyltransferase Pcif1 Activity On Uncapped Rnas, Dan Yu, Nan Dai, Eric J Wolf, Ivan R Corrêa, Jujun Zhou, Tao Wu, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

The phosphorylated RNA polymerase II CTD interacting factor 1 (PCIF1) is a methyltransferase that adds a methyl group to the N6-position of 2′O-methyladenosine (Am), generating N6, 2′O-dimethyladenosine (m6Am) when Am is the cap-proximal nucleotide. In addition, PCIF1 has ancillary methylation activities on internal adenosines (both A and Am), although with much lower catalytic efficiency relative to that of its preferred cap substrate. The PCIF1 preference for 2′O-methylated Am over unmodified A nucleosides is due mainly to increased binding affinity for Am. Importantly, it was recently reported that PCIF1 can methylate viral RNA. Although some viral RNA can be translated in …

Loss Of Rnf43 Accelerates Kras-Mediated Neoplasia And Remodels The Tumor Immune Microenvironment In Pancreatic Adenocarcinoma, Abdel Nasser Hosein, Gita Dangol, Takashi Okumura, Jason Roszik, Kimal Rajapakshe, Megan Siemann, Mohamed Zaid, Bidyut Ghosh, Maria Monberg, Paola A Guerrero, Aatur Singhi, Cara L Haymaker, Hans Clevers, Lotfi Abou-Elkacem, Sonja M Woermann, Anirban Maitra

Faculty, Staff and Student Publications

Background & aims: RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been characterized sufficiently. In this study, we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 in exocrine cells.

Methods: We generated Ptf1a-Cre;LSL-KrasG12D;Rnf43flox/flox (KRC) and Ptf1a-Cre; LSL-KrasG12D (KC) mice and animal survival was assessed. KRC mice were sacrificed at 2 months, 4 months, and at moribund …