Article
Cell Biology
Jian Carrot-Zhang, Xiaotong Yao, Siddhartha Devarakonda, Aditya Deshpande, Jeffrey S. Damrauer, Tiago Chedraoui Silva, Christopher K. Wong, Hyo Young Choi, Ina Felau, A. Gordon Robertson, Mauro A. A. Castro, Lisui Bao, Esther Rheinbay, Eric Minwei Liu, Tuan Trieu, David Haan, Christina Yau, Toshinori Hinoue, Yuexin Liu, Ofer Shapira, Kiran Kumar, Karen L. Mungall, Hailei Zhang, Jake June-Koo Lee, Ashton Berger, Galen F. Gao, Binyamin Zhitomirsky, Wen-Wei Liang, Meng Zhou, Sitapriya Moorthi, Alice H. Berger, Eric A. Collisson, Michael C. Zody, Li Ding, Andrew D. Cherniack, Gad Getz, Olivier Elemento, Christopher C. Benz, Josh Stuart, J. C. Zenklusen, Rameen Beroukhim, Jason C. Chang, Joshua D. Campbell, D. Neil Hayes, Lixing Yang, Peter W. Laird, John N. Weinstein, David J. Kwiatkowski, Ming S. Tsao, William D. Travis, Ekta Khurana, Benjamin P. Berman, Katherine A. Hoadley, Nicolas Robine, Matthew Meyerson, Ramaswamy Govindan, Marcin Imielinski
Summary: Alterations in the RTK/RAS/RAF pathway are a characteristic feature of lung adenocarcinoma (LUAD). A study using whole-genome sequencing of 85 cases initially identified as RPA(-) revealed that around 33% of cases were actually RPA(+). The remaining cases showed genetic mutations associated with tumor suppressor deletions and genome instability.
Article
Pharmacology & Pharmacy
Chuanhui Chen, Pinglang Zhou, Zhizhe Zhang, Yu Liu
Summary: The U2AF1-S34F mutation results in mis-splicing of DNA damage repair genes, increasing sensitivity to RAD51 inhibition in lung cancer cells.
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
(2022)
Article
Oncology
Khaled Alayed, Howard J. Meyerson
Summary: A decreased percentage of CD177(pos) neutrophils is frequently present in MDS and AML and is associated with somatic mutations involving several genes.
Article
Multidisciplinary Sciences
Raisa A. Reyes-Castro, Shin-Yu Chen, Jacob Seemann, Samrat T. Kundu, Don L. Gibbons, Swathi Arur
Summary: The KRAS/ERK pathway phosphorylates DICER1, leading to its nuclear translocation, and phosphomimetic Dicer1 promotes tumorigenesis in mice. However, the mechanisms by which phospho-DICER1 regulates tumor progression are not fully understood. In this study, we discovered that phosphorylated nuclear DICER1 (phospho-nuclear DICER1) promotes late-stage tumor progression in mice with oncogenic Kras, independent of microRNAs (miRNAs) and epithelial-to-mesenchymal transition (EMT). Our findings suggest that phospho-nuclear DICER1 plays a role in lineage reprogramming of tumor cells to mediate lung cancer progression.
Article
Biochemistry & Molecular Biology
Giulia Biancon, Poorval Joshi, Joshua T. Zimmer, Torben Hunck, Yimeng Gao, Mark D. Lessard, Edward Courchaine, Andrew E. S. Barentine, Martin Machyna, Valentina Botti, Ashley Qin, Rana Gbyli, Amisha Patel, Yuanbin Song, Lea Kiefer, Gabriella Viero, Nils Neuenkirchen, Haifan Lin, Joerg Bewersdorf, Matthew D. Simon, Karla M. Neugebauer, Toma Tebaldi, Stephanie Halene
Summary: Splicing factor mutations, especially in U2AF1, are common drivers of myeloid malignancies, affecting the splicing process and leading to intron retention and exon exclusion. In addition, U2AF1 mutations directly influence the components of stress granules, which are involved in adaptive oncogenic strategies in cancer cells.
Article
Medicine, Research & Experimental
Brian A. Wadugu, Sridhar Nonavinkere Srivatsan, Amanda Heard, Michael O. Alberti, Matthew Ndonwi, Jie Liu, Sarah Grieb, Joseph Bradley, Jin Shao, Tanzir Ahmed, Cara L. Shirai, Ajay Khanna, Dennis L. Fei, Christopher A. Miller, Timothy A. Graubert, Matthew J. Walter
Summary: Research indicates that deletion of the wild-type allele in hematopoietic cells expressing U2AF1(S34F) heterozygous mutation is lethal, confirming the dependence of mutant U2AF1 cells on the expression of wild-type U2AF1 for survival. Leukemia cells carrying mutant U2AF1 are more sensitive to reduced wild-type U2AF1 expression, suggesting a potential therapeutic strategy for selectively targeting the wild-type U2AF1 allele in mutant cells.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Oncology
Avik Dutta, Yue Yang, Bao T. Le, Yifan Zhang, Omar Abdel-Wahab, Chongzhi Zang, Golam Mohi
Summary: The study reveals the crucial role of U2AF1 in normal hematopoiesis, as its deletion leads to loss of hematopoietic stem/progenitor cells and increased DNA damage. RNA sequencing analysis shows significant alterations in genes related to HSC maintenance, cell proliferation, and DNA damage response in U2AF1-deficient HSPC, as well as splicing alterations in genes important for HSPC function.
Article
Cell Biology
Sanghyun P. Kim, Sridhar N. Srivatsan, Monique Chavez, Cara L. Shirai, Brian S. White, Tanzir Ahmed, Michael O. Alberti, Jin Shao, Ryan Nunley, Lynn S. White, Jeff Bednarski, John R. Pehrson, Matthew J. Walter
Summary: Somatic mutations in spliceosome genes are found in around 50% of patients with myelodysplastic syndromes (MDS), a myeloid malignancy associated with low blood counts. The mutant splicing factor U2AF1(S34F) alters hematopoiesis and mRNA splicing in mice. Alternative splicing of spliceosome genes has been implicated in hematopoietic abnormalities.
Article
Biochemistry & Molecular Biology
Yuanqing Feng, Hongzhan Xu, Jinghao Liu, Ning Xie, Lei Gao, Yanyun He, Yuan Yao, Fengxiang Lv, Yan Zhang, Jian Lu, Wei Zhang, Chuan-Yun Li, Xinli Hu, Ziheng Yang, Rui-Ping Xiao
Summary: Cis-regulatory elements play crucial roles in tissue-specific gene expression and phenotype evolution. Mutations in promoters and enhancers may drive species adaptations to environments. TRIM72, a highly conserved protein involved in energy metabolism, shows varying levels of expression in primate hearts, with mutations in the promoter being responsible for these differences. Accelerated rates of evolution in the TRIM72 promoter suggest positive selection influenced by changes in cardiac physiology after species divergence. Mutations in the TRIM72 promoter account for differential expression in human and rhesus macaque hearts, affecting genes involved in oxidative phosphorylation, mitochondrial respiration, and cardiac energy capacity. Phylogenetic regression analyses indicate a correlation between high cardiac TRIM72 expression and heart rate in mammals.
MOLECULAR BIOLOGY AND EVOLUTION
(2021)
Article
Biochemistry & Molecular Biology
Lorenz M. Bell, Annegret Holm, Uta Matysiak, Wolfgang Driever, Jochen Roessler, Denny Schanze, Ilse Wieland, Charlotte M. Niemeyer, Martin Zenker, Friedrich G. Kapp
Summary: This study investigates the pathogenic factors of vascular malformations, the impact of mutations on the type of malformation, and the use of a zebrafish model for evaluating pathogenicity of mutations and testing candidate drugs in a personalized and mutation-specific approach.
HUMAN MOLECULAR GENETICS
(2022)
Article
Oncology
Amber Johnson, Patrick Kwok-Shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Yujia Wang, Jia Zeng, Vijaykumar Holla, Thuy Vu, Fei Su, Sun-Hee Kim, Tara Conway, Xianli Jiang, Ken Chen, Kenna R. Mills Shaw, Timothy A. A. Yap, Jordi Rodon, Gordon B. B. Mills, Funda Meric-Bernstam
Summary: Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either Unknown or Potentially actionable based on their location within functional domains and/or proximity to known oncogenic variants. Our results demonstrate that rule-based actionability classification of VUS can identify patients more likely to have actionable variants for consideration with genomically-matched therapy.
NPJ PRECISION ONCOLOGY
(2023)
Article
Oncology
Min Tang, Juan Chen, Tian Zeng, Dong-mei Ye, Yu-kun Li, Juan Zou, Yu-ping Zhang
Summary: DNA replication alteration is frequently observed in lung adenocarcinoma (LUAD) progression. The ORC, especially ORC1/6, has important prognostic and expression significance for LUAD patients. Furthermore, the ORC cooperatively promotes LUAD development by driving DNA replication, cellular senescence, and metabolic processes.
Article
Oncology
Huashan Shi, Karan Seegobin, Fei Heng, Kexun Zhou, Ruqin Chen, Hong Qin, Rami Manochakian, Yujie Zhao, Yanyan Lou
Summary: The genomic characteristics of lung adenocarcinoma vary significantly among different racial groups, with the EGFR and KRAS genes showing the highest discrepancies. This data will contribute to the understanding of molecular alterations and their impacts on clinical management in different lung cancer patients.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Xiangxiang Jiang, Na Qin, Tingting Hua, Xiaoxia Wei, Yuancheng Li, Congcong Chen, Linnan Gong, Su Liu, Cheng Wang, Rong Yin, Yue Jiang, Juncheng Dai, Lin Xu, Hongbing Shen, Hongxia Ma
Summary: This study provides a comprehensive characterization of super-enhancers (SEs) in lung adenocarcinoma (LUAD) and emphasizes their clinical significance in LUAD therapy. The findings highlight the different regulatory mechanisms of SEs in cancer compared to normal SEs and their association with crucial tumor-related pathways.
MOLECULAR CARCINOGENESIS
(2022)
Article
Medicine, Research & Experimental
Marina Salmon, Ruth Alvarez-Diaz, Coral Fustero-Torre, Oksana Brehey, Carmen G. Lechuga, Manuel Sanclemente, Fernando Fernandez-Garcia, Alejandra Lopez-Garcia, Maria Carmen Martin-Guijarro, Sandra Rodriguez-Perales, Emily Bousquet-Mur, Lucia Morales-Cacho, Francisca Mulero, Fatima Al-Shahrour, Lola Martinez, Orlando Dominguez, Eduardo Caleiras, Sagrario Ortega, Carmen Guerra, Monica Musteanu, Matthias Drosten, Mariano Barbacid
Summary: KRASG12C inhibitors have greatly improved the clinical management of KRASG12C-mutant lung adenocarcinoma patients, but resistance develops rapidly. In this study, genetically engineered mice were used to compare the efficacy and resistance between genetic ablation and pharmacological inhibition of mutant Kras. Results showed that Kras ablation effectively regressed tumors and prevented resistant cells, while treatment with sotorasib, a selective KRASG12C inhibitor, led to limited antitumor response and rapid onset of resistance. Unlike human tumors, resistance in mice was not due to mutations in RAS signaling pathways, but rather amplification of mutant Kras allele and activation of xenobiotic metabolism pathways.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Review
Pathology
Joseph G. Schroers-Martin, Stefan Alig, Andrea Garofalo, Benoit Tessoulin, Takeshi Sugio, Ash A. Alizadeh
Summary: Molecular monitoring plays a crucial role in the surveillance and clinical management of lymphomas, aided by the high concentration of cell-free DNA and circulating tumor DNA, high somatic mutational burden, and presence of recurrently altered regions. This review summarizes the current evidence on molecular subtyping, classification, treatment response evaluation, surveillance of cellular therapies, and emerging clinical trial strategies for lymphomas.
ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE
(2023)
Review
Chemistry, Multidisciplinary
Reese M. Caldwell, Ryan A. Flynn
Summary: Chemical biology has made a significant impact on glycobiology, allowing researchers to study the structure, functions, and regulation of complex glycans using bioorthogonal chemistry and metabolic chemical reporters. The use of Ac(4)ManNAz has revolutionized the discovery of glycosylated RNA and expanded our understanding of RNA post-transcriptional modifications.
ISRAEL JOURNAL OF CHEMISTRY
(2023)
Article
Oncology
Brian J. Sworder, David M. Kurtz, Stefan K. Alig, Matthew J. Frank, Navika Shukla, Andrea Garofalo, Charles W. Macaulay, Mohammad Shahrokh Esfahani, Mari N. Olsen, James Hamilton, Hitomi Hosoya, Mark Hamilton, Jay Y. Spiegel, John H. Baird, Takeshi Sugio, Mia Carleton, Alexander F. M. Craig, Sheren F. Younes, Bita Sahaf, Natasha D. Sheybani, Joseph G. Schroers-Martin, Chih Long Liu, Jean S. Oak, Michael C. Jin, Sara Beygi, Andreas Huttmann, Christine Hanoun, Ulrich Duhrsen, Jason R. Westin, Michael S. Khodadoust, Yasodha Natkunam, Robbie G. Majzner, Crystal L. Mackall, Maximilian Diehn, David B. Miklos, Ash A. Alizadeh
Summary: This study investigates the resistance of anti-CD19 chimeric antigen receptor (CAR19) T cells in relapsed/refractory large B-cell lymphoma (r/rLBCL) patients. By analyzing longitudinal samples from two independent cohorts, it identifies multiple gene alterations associated with resistance, such as B cell identity genes (PAX5 and IRF8), immune checkpoint genes (CD274), and genes affecting the tumor microenvironment (TMEM30A). It also reveals that somatic tumor alterations affect CAR19 therapy at various levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. These findings have implications for improving CAR T cells and personalized therapeutic approaches.
Article
Oncology
Jurik A. Mutter, Stefan K. Alig, Mohammad S. Esfahani, Eliza M. Lauer, Jan Mitschke, David M. Kurtz, Julia Kuehn, Sabine Bleul, Mari Olsen, Chih Long Liu, Michael C. C. Jin, Charles W. Macaulay, Nicolas Neidert, Timo Volk, Michel Eisenblaetter, Sebastian Rauer, Dieter H. Heiland, Jurgen Finke, Justus Duyster, Julius Wehrle, Marco Prinz, Gerald Illerhaus, Peter C. Reinacher, Elisabeth Schorb, Maximilian Diehn, Ash A. Alizadeh, Florian Scherer
Summary: We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification. CtDNA was detectable in 78% of pretreatment plasma and 100% of CSF samples. Presence of ctDNA in pretreatment plasma was associated with shorter progression-free survival and overall survival. Monitoring ctDNA during treatment identified patients with poor prognosis. We developed a machine learning approach for biopsy-free CNSL identification from ctDNA.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
News Item
Chemistry, Multidisciplinary
Christopher P. P. Watkins, Ryan A. A. Flynn
Summary: Interactions between proteins and non-proteinaceous biopolymers are crucial for life, but current methods for characterizing these interactions are imprecise and biased. A genetically encoded method based on sulfur(vi) fluoride exchange (SuFEx) has been developed to capture and analyze protein-RNA and protein-carbohydrate interactions in vivo.
Article
Hematology
Ryan C. Lynch, Christina Poh, Chaitra S. Ujjani, Edus H. Warren III, Stephen D. Smith, Mazyar Shadman, Karolyn Morris, Sydney Lee, Heather Rasmussen, Susan Ottemiller, Megan Shelby, Sarith Keo, Kaitlin Verni, David M. Kurtz, Ash A. Alizadeh, Jacob J. Chabon, Gregory J. Hogan, Andre Schulz, Ted Gooley, Jenna M. Voutsinas, Ajay K. Gopal
Summary: The POLARIX trial showed the superiority of Pola over vincristine in the RCHOP regimen for large B-cell lymphomas, but its safety in intensified regimens is unknown. This study evaluated the safety and efficacy of Pola-DA-EPCH-R in aggressive large B-cell lymphomas.
Article
Hematology
Hua-Jay J. Cherng, Stefan K. Alig, Yasuhiro Oki, Loretta J. Nastoupil, Luis Fayad, Sattva S. Neelapu, Francesco Turturro, Fredrick Hagemeister, Alexander F. M. Craig, Charles W. Macaulay, Maria Alma Rodriguez, Hun Ju Lee, Timothy J. McDonnell, Christopher R. Flowers, Francisco Vega, Michael R. Green, Lei Feng, David M. Kurtz, Ash A. Alizadeh, R. Eric Davis, Jason R. Westin
Summary: LO-CHOP treatment shows high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of overall and complete response. It is a potentially effective and well-tolerated treatment option.
Article
Hematology
Ryan C. Lynch, Chaitra S. Ujjani, Christina Poh, Edus H. Warren, Stephen D. Smith, Mazyar Shadman, Brian Till, Vikram M. Raghunathan, Stefan Alig, Ash A. Alizadeh, Avanti Gulhane, Delphine L. Chen, Yolanda Tseng, Hilary Coye, Megan Shelby, Susan Ottemiller, Sarith Keo, Kaitlin Verni, Hongyan Du, Jacquelin Vandermeer, Ashley Gaston, Heather Rasmussen, Paul Martin, Edmond Marzbani, Jenna Voutsinas, Ajay K. Gopal
Summary: This study investigated the concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma, showing promising safety and efficacy. Although some patients experienced adverse events, the overall response rate was 100% with a complete response rate of 90%.
Review
Biochemistry & Molecular Biology
Kyle Swanson, Eric Wu, Angela Zhang, Ash A. Alizadeh, James Zou
Summary: Machine learning is increasingly used in clinical oncology to diagnose cancers, predict patient outcomes, and inform treatment planning. This review focuses on recent applications of machine learning across the clinical oncology workflow, including medical imaging and molecular data obtained from liquid and solid tumor biopsies for cancer diagnosis, prognosis, and treatment design. Key considerations in developing machine learning for the distinct challenges posed by imaging and molecular data are discussed. The review also examines machine learning models approved for cancer-related patient usage by regulatory agencies and discusses approaches to improve the clinical usefulness of machine learning.
Article
Oncology
Joseph G. Schroers-Martin, Joanne Soo, Gabriel Brisou, Florian Scherer, David M. Kurtz, Brian J. Sworder, Michael S. Khodadoust, Michael C. Jin, Agnes Bru, Chih Long Liu, Henning Stehr, Paolo Vineis, Yasodha Natkunam, Lauren R. Teras, Joo Y. Song, Bertrand Nadel, Maximilian Diehn, Sandrine Roulland, Ash A. Alizadeh
Summary: Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals, suggesting additional lesions are required for lymphomagenesis. CREBBP KAT domain mutations were the most commonly observed precursor lesions, distinguishing patients developing FL from healthy adults with or without BCL2 rearrangements. These mutations can be detected years before clinical diagnosis and may help discriminate individuals at risk for lymphoma development.
Article
Hematology
Patricia Johansson, Stefan Alig, Julia Richter, Christine Hanoun, Jan Rekowski, Jan Duerig, Bauke Ylstra, Daphne de Jong, Wolfram Klapper, Ash A. Alizadeh, Ulrich Duehrsen, Andreas Huettmann
Summary: In DLBCL, a positive interim PET scan predicts treatment failure, and combining it with the presence of an IgM gammopathy can improve prediction. The combination of interim PET and IgM gammopathy can dichotomize the population into high-risk and low-risk groups with significantly different outcomes. Only the interim PET result and IgM gammopathy status were significantly associated with outcome, making them important factors in risk-adapted treatment strategies.
ANNALS OF HEMATOLOGY
(2023)
Article
Oncology
Nirakar Rajbhandari, Michael Hamilton, Cynthia M. Quintero, L. Paige Ferguson, Raymond Fox, Christian M. Schuerch, Jun Wang, Mari Nakamura, Nikki K. Lytle, Matthew Mcdermott, Emily Diaz, Hannah Pettit, Marcie Kritzik, Haiyong Han, Derek Cridebring, Kwun Wah Wen, Susan Tsai, Michael G. Goggins, Andrew M. Lowy, Robert J. Wechsler-Reya, Daniel D. Von Hoff, Aaron M. Newman, Tannishtha Reya
Summary: Through single-cell genomics analysis, this study reveals that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ pancreatic cells, which establish different subtypes by activating distinct transcriptional programs and large-scale genomic changes.
Article
Multidisciplinary Sciences
Alyssa M. Kaiser, Alberto Gatto, Kathryn J. Hanson, Richard L. Zhao, Nitin Raj, Michael G. Ozawa, Jose A. Seoane, Kathryn T. Bieging-Rolett, Mengxiong Wang, Irene Li, Winston L. Trope, Douglas Z. Liou, Joseph B. Shrager, Sylvia K. Plevritis, Aaron M. Newman, Capucine Van Rechem, Laura D. Attardi
Summary: Lung cancer is the leading cause of cancer deaths worldwide, and mutations in the TP53 gene are linked to poor prognosis in lung adenocarcinomas (LUADs). This study reveals that p53 suppresses LUAD by promoting alveolar type 1 (AT1) differentiation. Through direct DNA binding, chromatin remodeling, and induction of AT1 cell characteristic genes, p53 induces an AT1 differentiation program during tumor suppression. Additionally, p53 plays a role in alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells.
Editorial Material
Biotechnology & Applied Microbiology
Petar Hristov, Ryan A. Flynn
Summary: Proximity ligation is utilized to study a recently discovered RNA species on the cell surface.
NATURE BIOTECHNOLOGY
(2023)
Article
Oncology
Eliza M. Lauer, Ella Riegler, Jurik A. Mutter, Stefan K. Alig, Sabine Bleul, Julia Kuehn, Lavanya Ranganathan, Christian Klingler, Theo Demerath, Urs Wuertemberger, Alexander Rau, Jakob Weiss, Michel Eisenblaetter, Fabian Bamberg, Marco Prinz, Juergen Finke, Justus Duyster, Gerald Illerhaus, Maximilian Diehn, Ash A. Alizadeh, Elisabeth Schorb, Peter C. Reinacher, Florian Scherer
Summary: The study found that the use of semi-automated three-dimensional tumor volume measurements can serve as strong and independent early predictors of clinical outcomes in central nervous system lymphoma (CNSL) patients. These radiologic features can help improve risk stratification and guide future treatment approaches.
