Article
Multidisciplinary Sciences
Kee-Beom Kim, Ashish Kabra, Dong-Wook Kim, Yongming Xue, Yuanjian Huang, Pei-Chi Hou, Yunpeng Zhou, Leilani J. Miranda, Jae-Il Park, Xiaobing Shi, Timothy P. Bender, John H. Bushweller, Kwon-Sik Park
Summary: EP300, an important transcription coactivator in proliferation and differentiation, is frequently mutated in various cancer types. This study found that EP300 mutants without acetyltransferase domain accelerate tumor development in small cell lung cancer (SCLC) mouse models, while complete EP300 knockout suppresses SCLC development and proliferation. The kinase inducible domain-interacting (KIX) domain of EP300, specifically its interaction with transcription factors including MYB, was identified as the determinant of protumorigenic activity. Inhibition of KIX-mediated interactions inhibits SCLC development and cell growth.
Article
Biochemistry & Molecular Biology
Alexandra D. Brown, Connor Cranstone, Denis J. Dupre, David N. Langelaan
Summary: The study investigates the interaction between β-catenin and CBP/p300, and determines that the C-terminal region of β-catenin binds to the TAZ1 and TAZ2 domains of CBP/p300. The results provide insights into the gene regulation mechanism of β-catenin and offer a framework for developing methods to block β-catenin dependent signaling.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biology
Sumiko Takao, Lauren Forbes, Masahiro Uni, Shuyuan Cheng, Jose Mario Bello Pineda, Yusuke Tarumoto, Paolo Cifani, Gerard Minuesa, Celine Chen, Michael G. Kharas, Robert K. Bradley, Christopher R. Vakoc, Richard P. Koche, Alex Kentsis
Summary: The dysregulated gene expression in human cancers is often attributed to aberrant assembly of transcriptional co-activator complexes, as demonstrated in the case of acute myeloid leukemia (AML) subtypes. Targeted interference with MYB:CBP/P300 complexes can induce myeloid differentiation and apoptosis, providing a unified mechanism for oncogenic gene expression in AML. This study establishes a promising strategy for pharmacologic reprogramming and therapeutic targeting in diverse leukemias and potentially other human cancers.
Article
Biochemistry & Molecular Biology
Matthew Jones, Philipp Grosche, Andreas Floersheimer, Jerome Andre, Raphael Gattlen, Dieter Oser, Juliette Tinchant, Roman Wille, Barbara Chie-Leon, Marc Gerspacher, Peter Ertl, Nils Ostermann, Eva Altmann, Eusebio Manchado, Thomas Vorherr, Patrick Chene
Summary: The Myb transcription factor plays a role in the proliferation of hematopoietic cells and its abnormal expression can cause cancers such as leukemia. It interacts with various proteins, including the histone acetyltransferases p300 and CBP. In this study, researchers designed Myb-derived peptides that interact with the p300KIX domain and found peptidic inhibitors that bind much tighter to p300KIX than wildtype Myb. This suggests the potential for designing low molecular-weight compounds to disrupt the Myb/p300KIX interaction.
Article
Oncology
Daria Frank, Ramkumar Moorthy, John C. Widen, Cyrus Khandanpour, Daniel A. Harki, Karl-Heinz Klempnauer, Luca Abdel Ghani, Maria V. Yusenko, Wolfgang Doerner
Summary: C/EBP β is a transcription factor that cooperates with MYB to maintain proliferation and differentiation block of AML cells. A synthetic analog of helenalin inhibits C/EBP β by covalently binding to cysteine residues in the transactivation domain, leading to enhanced differentiation, cell death, and reduced self-renewal potential of AML cells. Gene expression profiling confirms the relevance of C/EBP β as a therapeutic target. However, further development is needed to improve the effectiveness of the synthetic analog as a C/EBP β inhibitor.
Article
Chemistry, Multidisciplinary
Stephen T. Joy, Matthew J. Henley, Samantha N. De Salle, Matthew S. Beyersdorf, Isaac W. Vock, Allison J. L. Huldin, Anna K. Mapp
Summary: MybLL-tide is a picomolar dual-site inhibitor of the Myb-CBP/p300 KIX interaction, showing high affinity and selectivity, effectively inhibiting key genes in AML cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Meghan E. Breen, Stephen T. Joy, Omari J. Baruti, Matthew S. Beyersdorf, Madeleine J. Henley, Samantha N. De Salle, Peter D. Ycas, Ayza Croskey, Tomasz Cierpicki, William C. K. Pomerantz, Anna K. Mapp
Summary: Natural product garcinolic acid blocks CBP/p300 KIX PPI network by strong interaction with a non-canonical binding site, inhibiting KIX-dependent transcription in leukemia. It selectively engages CBP/p300 KIX domain, disrupting its protein-protein interactions and downregulating essential transcriptional circuits for cMyb-dependent leukemias.
Article
Oncology
Tao Zhang, Bofang Wang, Baohong Gu, Fei Su, Lin Xiang, Le Liu, Xuemei Li, Xueyan Wang, Lei Gao, Hao Chen
Summary: This research systematically analyzed the molecular alterations and clinical relevance of histone acetyltransferase (HAT) and histone deacetylase (HDAC) genes in five types of digestive cancers. It found recurrent mutations and copy number variations in acetylation-associated genes, and identified their correlation with cancer hallmark-related pathways. The expression pattern of these genes stratified patients' clinical benefit in hepatocellular carcinoma and pancreatic cancer.
JOURNAL OF ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shelby E. Compton, Susan M. Kitchen-Goosen, Lisa M. DeCamp, Kin H. Lau, Batsirai Mabvakure, Matthew Vos, Kelsey S. Williams, Kwok-Kin Wong, Xiaobing Shi, Scott B. Rothbart, Connie M. Krawczyk, Russell G. Jones
Summary: In this study, the researchers identified CRTC2 as an epigenetic driver of inflammatory potential downstream of LKB1 mutations. They found that LKB1 loss sensitizes cells to inflammatory stimuli, leading to increased production of cytokines and chemokines. Mechanistically, CRTC2 cooperates with CBP/p300 to deposit histone acetylation marks at inflammatory gene loci, promoting cytokine expression.
Article
Chemistry, Medicinal
Jonathan E. Sandoval, Raghav Ramabadran, Nathaniel Stillson, Letitia Sarah, Danica Galonic Fujimori, Margaret A. Goodell, Norbert Reich
Summary: This study identified two novel small molecule compounds that disrupt protein-protein interactions involving DNMT3A, leading to cell differentiation and potential treatment for diseases associated with aberrant DNMT3A interactions, such as acute myeloid leukemia.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biophysics
Jae-Sook Ahn, TaeHyung Kim, Sung-Hoon Jung, Seo-Yeon Ahn, Seung-Yeon Jung, Ga-Young Song, Mihee Kim, Deok-Hwan Yang, Je-Jung Lee, SeungHyun Choi, Ja-Yeon Lee, Seong-Kyu Park, Joon Ho Moon, Hui Young Lee, Kyoung Ha Kim, Yu Cai, Seong Yoon Yi, Igor Novitzky-Basso, Zhaolei Zhang, Hyeoung-Joon Kim, Dennis Dong Hwan Kim
Summary: The study suggests that allogeneic HCT may be more beneficial than chemotherapy for consolidation therapy in NK-AML patients with detectable MRD by NGS in CR1. Further randomized clinical trials are needed to confirm these findings.
BONE MARROW TRANSPLANTATION
(2021)
Article
Neurosciences
Hideo Hagihara, Vibeke S. Catts, Yuta Katayama, Hirotaka Shoji, Tsuyoshi Takagi, Freesia L. Huang, Akito Nakao, Yasuo Mori, Kuo-Ping Huang, Shunsuke Ishii, Isabella A. Graef, Keiichi I. Nakayama, Cynthia Shannon Weickert, Tsuyoshi Miyakawa
NEUROPSYCHOPHARMACOLOGY
(2018)
Article
Biochemistry & Molecular Biology
David van Dijk, Roshan Sharma, Juozas Nainys, Kristina Yim, Pooja Kathail, Ambrose J. Carr, Cassandra Burdziak, Kevin R. Moon, Christine L. Chaffer, Diwakar Pattabiraman, Brian Bierie, Linas Mazutis, Guy Wolf, Smita Krishnaswamy, Dana Pe'er
Article
Biochemistry & Molecular Biology
Toshio Maekawa, Binbin Liu, Daisuke Nakai, Keisuke Yoshida, Ken-ichi Nakamura, Mami Yasukawa, Manabu Koike, Kaiyo Takubo, Bruno Chatton, Fuyuki Ishikawa, Kenkichi Masutomi, Shunsuke Ishii
NUCLEIC ACIDS RESEARCH
(2018)
Article
Oncology
S. Y. N. Jamaludin, I. Azimi, F. M. Davis, A. A. Peters, T. J. Gonda, E. W. Thompson, S. J. Roberts-Thomson, G. R. Monteith
Letter
Oncology
Kyaw Ze Ya Maung, Paul J. Leo, Mahmoud Bassal, Debora A. Casolari, James X. Gray, Sarah C. Bray, Stephen Pederson, Deepak Singhal, Saumya E. Samaraweera, Tran Nguyen, Gokhan Cildir, Mhairi Marshall, Adam Ewing, Emma L. Duncan, Matthew A. Brown, Russell Saal, Vinay Tergaonkar, Luen Bik To, Paula Marlton, Devinder Gill, Ian Lewis, Andrew J. Deans, Anna L. Brown, Richard J. D'Andrea, Thomas J. Gonda
BLOOD CANCER JOURNAL
(2018)
Article
Biochemistry & Molecular Biology
Ren-Ming Yang, Devathri Nanayakkara, Murugan Kalimutho, Partha Mitra, Kum Kum Khanna, Eloise Dray, Thomas J. Gonda
Article
Cell Biology
Toshio Maekawa, Binbin Liu, Yang Liu, Keisuke Yoshida, Masafumi Muratani, Bruno Chatton, Shunsuke Ishii
Article
Genetics & Heredity
Nhung Hong Ly, Toshio Maekawa, Keisuke Yoshida, Yang Liu, Masafumi Muratani, Shunsuke Ishii
G3-GENES GENOMES GENETICS
(2019)
Article
Multidisciplinary Sciences
Lu Cao, Partha Mitra, Thomas J. Gonda
SCIENTIFIC REPORTS
(2019)
Article
Cell Biology
Nevena B. Ognjenovic, Meisam Bagheri, Gadisti Aisha Mohamed, Ke Xu, Youdinghuan Chen, Mohamed Ashick Mohamed Saleem, Meredith S. Brown, Shivashankar H. Nagaraj, Kristen E. Muller, Scott A. Gerber, Brock C. Christensen, Diwakar R. Pattabiraman
DEVELOPMENTAL CELL
(2020)
Article
Hematology
Saumya E. Samaraweera, Paul P. S. Wang, Ka Leung Li, Debora A. Casolari, Jinghua Feng, Mark Pinese, Kyaw Ze Ya Maung, Paul Leo, Mark Cowley, Kelly Perkins, Amanda M. Smith, Jonathan Ellis, Amilia Wee, Devendra K. Hiwase, Hamish S. Scott, Andreas W. Schreiber, Anna L. Brown, Andrew J. Deans, David M. Ross, Andrew S. Moore, Thomas J. Gonda, Christopher N. Hahn, Richard J. Andrea
Article
Oncology
Meredith S. Brown, Kristen E. Muller, Diwakar R. Pattabiraman
Summary: The epithelial-to-mesenchymal transition (EMT) and its reversal, the mesenchymal-to-epithelial transition (MET), play critical roles in the metastasis of breast cancer and other solid tumors. However, defining and quantifying EMT status is not commonly used in clinical practice. Therefore, identifying and measuring the presence of different EMT states in tumors is a crucial first step in evaluating patient prognosis.
Article
Genetics & Heredity
Min Kyung Lee, Meredith S. Brown, Owen M. Wilkins, Diwakar R. Pattabiraman, Brock C. Christensen
Summary: The study indicates the importance of both distinct and shared epigenetic profiles associated with EMT processes, which may be targeted to prevent EMT progression.
Article
Multidisciplinary Sciences
Mahmoud A. Bassal, Saumya E. Samaraweera, Kelly Lim, Brooks A. Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A. Casolari, Diana G. Iarossi, Ilaria S. Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D. Lewis, Anna L. Brown, Daniel G. Tenen, Nirmal Robinson, David M. Ross, Ravindra Majeti, Thomas J. Gonda, Daniel Thomas, Richard J. D'Andrea
Summary: This study reveals the mutual exclusivity between germline mutations in mitochondrial complex I and somatic mutations in the metabolic enzyme IDH1 in patients with acute myeloid leukemia (AML), and finds that IDH1 mutant cells have increased sensitivity to complex I inhibitors.
NATURE COMMUNICATIONS
(2022)
Editorial Material
Hematology
Thomas J. Gonda
Summary: Clarke et al(1) demonstrate in this study that loss of 1 allele of Myb in mice leads to increased myeloproliferation and development of myeloid neoplasms, including AML, during aging. This is surprising given the established role of MYB in normal hematopoiesis and leukemogenesis. These findings suggest that even partial loss of MYB activity can predispose individuals to myeloid neoplasms.