Review
Biochemistry & Molecular Biology
Ian G. Cowell, John W. Casement, Caroline A. Austin
Summary: Transcription and its regulation are affected by DNA torsion and supercoiling, which are resolved by DNA topoisomerases. This review focuses on one type of DNA topoisomerase II beta, which plays a critical role in developmental transcription and signal-induced transcription.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Franziska Liss, Miriam Frech, Ying Wang, Gavin Giel, Sabrina Fischer, Clara Simon, Lisa Marie Weber, Andrea Nist, Thorsten Stiewe, Andreas Neubauer, Andreas Burchert, Robert Liefke
Summary: The study identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans, demonstrating its critical role in regulating key signaling molecules, cell proliferation, and patient prognosis. High IRF8 expression is associated with poorer outcomes, indicating IRF8 as a potential biomarker and molecular target for a subset of AML cases.
Article
Oncology
Carla S. S. Walti, Anna B. B. Halpern, Hu Xie, Erika S. S. Kiem, E. Lisa Chung, Kelda G. G. Schonhoff, Emily M. M. Huebner, Colleen Delaney, Catherine Liu, Steven A. A. Pergam, Guang-Shing Cheng, Louise E. E. Kimball, Wendy M. M. Leisenring, Michael Boeckh, Roland B. B. Walter, Joshua A. A. Hill
Summary: Contemporary data on infections after intensive chemotherapy for acute myeloid leukemia (AML) are scarce. Patients receiving CLAG-M for newly diagnosed or relapsed/refractory AML have higher rates of moderate to severe infections, especially in the case of relapsed/refractory disease. Improved strategies for infection prevention are needed.
Article
Oncology
Wenchao Zhang, Panhong Gou, Jean-Marie Dupret, Christine Chomienne, Fernando Rodrigues-Lima
Summary: Etoposide, a widely used anticancer medicine, can induce therapy-related leukemia through its metabolites interacting with cellular proteins, leading to DNA double-stranded breaks and impairing enzyme activity.
TRANSLATIONAL ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Nikolai A. Lomov, Vladimir S. Viushkov, Sergey Ulianov, Alexey A. Gavrilov, Daniil A. Alexeyevsky, Artem Artemov, Sergey Razin, Mikhail A. Rubtsov
Summary: Topoisomerase inhibitors are commonly used in cancer chemotherapy, but they may cause acute leukemia as a long-term adverse effect. This study investigated the mechanisms behind therapy-induced acute myeloid leukemia (t-AML) by studying DNA break formation and mobility, as well as gene contacts. The results suggest that the separation and increased mobility of DNA break ends play a major role in the formation of recurrent t-AML translocations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Meng Li, Mingying Li, Yuan Xia, Guosheng Li, Xiuhua Su, Dongmei Wang, Jingjing Ye, Fei Lu, Tao Sun, Chunyan Ji
Summary: The study revealed that YY1 binds to the promoter region of METTL3 as a transcription factor and regulates METTL3 expression through LLPS, thereby affecting the proliferation of AML cells.
CELL DEATH & DISEASE
(2022)
Article
Hematology
Fraser Soares, Branson Chen, Jong Bok Lee, Musaddeque Ahmed, Dalam Ly, Enoch Tin, Hyeonjeong Kang, Yong Zeng, Nayeema Akhtar, Mark D. Minden, Housheng Hansen He, Li Zhang
Summary: AMl remains a devastating disease for which new therapies are needed. Targeted adoptive T-cell therapies have shown promise in some leukemias but not in AML. A study utilizing CRISPR/Cas9 screens identified SAGA and CD64 as key factors influencing the sensitivity of AML cells to DNT therapy.
Article
Hematology
Bo-Rui Chen, Anagha Deshpande, Karina Barbosa, Maria Kleppe, Xue Lei, Narayana Yeddula, Pablo Sanchez Vela, Alexandre Rosa Campos, Robert J. Wechsler-Reya, Anindya Bagchi, Soheil Meshinchi, Connie Eaves, Irmela Jeremias, Torsten Haferlach, David A. Frank, Ze'ev Ronai, Sumit Chanda, Scott A. Armstrong, Peter D. Adams, Ross L. Levine, Aniruddha J. Deshpande
Summary: Leukemias with AF10/MLLT10 gene fusions have a poor prognosis and currently lack targeted therapies. Research demonstrates that AF10 fusions activate JAK/STAT-mediated inflammatory signaling through recruitment of JAK1 kinase, and inhibition of this signaling pathway shows promising anti-cancer effects in AF10 fusion AML models. This study identifies JAK1 as a potential therapeutic target in AF10-rearranged leukemias.
Article
Oncology
Jian Hong, Leiming Xia, Zhenqi Huang, Xiaodong Yuan, Xinglin Liang, Jifei Dai, Zhonghui Wu, Li Liang, Min Ruan, Zhangbiao Long, Xin Cheng, Xiaowen Chen, Jing Ni, Jian Ge, Qingsheng Li, Qingshu Zeng, Ruixiang Xia, Yi Wang, Mingzhen Yang
Summary: The expression level of TIM-3 in AML blasts is significantly correlated with its expression in leukemic cells as well as CD8(+) and CD4(+) lymphocytes. TIM-3 expression in leukemic cells is significantly associated with core binding factor (CBF) translocations. However, the expression level of TIM-3 is not related to treatment response or prognosis in AML patients.
FRONTIERS IN ONCOLOGY
(2022)
Article
Cell Biology
Constantin Blochl, Di Wang, Katarina Madunic, Guinevere S. M. Lageveen-Kammeijer, Christian G. Huber, Manfred Wuhrer, Tao Zhang
Summary: AML presents challenges in treatment due to high rates of relapse or refractory disease. Recent studies have highlighted the importance of protein glycosylation in AML pathobiology, with specific glycan epitopes linked to disease outcome. This exploratory glycomics study identified distinct glycan structures in AML cell lines, providing insights into potential drivers of glycan phenotype.
Article
Oncology
Jessica M. Salmon, Izabela Todorovski, Kym L. Stanley, Claudia Bruedigam, Conor J. Kearney, Luciano G. Martelotto, Fernando Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A. Cluse, Peter J. Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y. Matthews, Elise Gressier, Nicole A. de Weerd, Jens Lichte, Madison J. Kelly, Simon J. Hogg, Paul J. Hertzog, Lev M. Kats, Stephin J. Vervoort, Daniel D. De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T. Kile, Steven W. Lane, Andrew C. Perkins, Andrew H. Wei, Pilar M. Dominguez, Ricky W. Johnstone
Summary: Inhibition of HDACs can induce differentiation and therapeutic effects in AML cells, and epigenetic rewiring of pDCs enhances antitumor immunity, offering a new therapeutic approach.
Article
Biochemistry & Molecular Biology
Simone S. Riedel, Congcong Lu, Hongbo M. Xie, Kevin Nestler, Marit W. Vermunt, Alexandra Lenard, Laura Bennett, Nancy A. Speck, Ichiro Hanamura, Julie A. Lessard, Gerd A. Blobel, Benjamin A. Garcia, Kathrin M. Bernt
Summary: MN1 overexpression in AML results in destabilization of enhancer chromatin by interacting with the myeloid progenitor specific BAF complex, leading to impaired myeloid differentiation and leukemia. The study also shows that overexpression of a polyQ protein, without coding sequence mutation, can be sufficient to cause malignant transformation.
Article
Hematology
Jose Tinajero, Dat Ngo, Amandeep Salhotra, Paul Koller
Summary: This study presents a CCE (cladribine, cytarabine, and etoposide) based regimen for relapsed/refractory acute myeloid leukemia (AML) patients. The regimen offers a potential option for patients who cannot tolerate anthracycline.
ACTA HAEMATOLOGICA
(2023)
Article
Hematology
Roger Mulet-Lazaro, Stanley van Herk, Claudia Erpelinck, Eric Bindels, Mathijs A. Sanders, Carlo Vermeulen, Ivo Renkens, Peter Valk, Ari M. Melnick, Jeroen de Ridder, Michael Rehli, Claudia Gebhard, Ruud Delwel, Bas J. Wouters
Summary: The study found that allele-specific expression of the GATA2 gene is closely associated with CEBPA double mutations, and may be acquired through mechanisms such as promoter methylation and overactivation, playing an important role in the development of AML.
Article
Oncology
Julia-Annabell Georgi, Sebastian Stasik, Jan-Niklas Eckardt, Sven Zukunft, Marita Hartwig, Christoph Roellig, Jan Moritz Middeke, Uta Oelschlaegel, Utz Krug, Tim Sauer, Sebastian Scholl, Andreas H. Hochhaus, Tim Bruemmendorf, Ralph Naumann, Bjoern Steffen, Hermann Einsele, Markus Schaich, Andreas Burchert, Andreas Neubauer, Kerstin Schaefer-Eckart, Christoph W. Schliemann, Stefan Krause, Mathias Haenel, Richard Noppeney, Ulrich D. Kaiser, Claudia Baldus, Martin Kaufmann, Carsten Mueller-Tidow, Uwe E. Platzbecker, Wolfgang Berdel, Hubert Serve, Gerhard Ehninger, Martin Bornhaeuser, Johannes Schetelig, Frank Kroschinsky, Christian Thiede
Summary: Tandem-duplication mutations of the UBTF gene are associated with pediatric AML patients and inferior outcomes. By screening adult AML and MDS patients, UBTF-TDs were found to be rare but more common in younger patients and associated with MDS-related morphology and lower hemoglobin and platelet levels. These mutations were also associated with specific co-mutations and were stable over the disease course, making them a novel class-defining lesion in both pediatric and younger adult AML patients.
BLOOD CANCER JOURNAL
(2023)
Article
Pharmacology & Pharmacy
Mandeep Atwal, Rebecca L. Swan, Chloe Rowe, Ka C. Lee, David C. Lee, Lyle Armstrong, Ian G. Cowell, Caroline A. Austin
MOLECULAR PHARMACOLOGY
(2019)
Article
Pharmacology & Pharmacy
Ian G. Cowell, Elise M. Ling, Rebecca L. Swan, Matilda L. W. Brooks, Caroline A. Austin
MOLECULAR PHARMACOLOGY
(2019)
Article
Biochemistry & Molecular Biology
Mushtaq M. Khazeem, Ian G. Cowell, Lauren F. Harkin, John W. Casement, Caroline A. Austin
Article
Pharmacology & Pharmacy
Rebecca L. Swan, Luke L. K. Poh, Ian G. Cowell, Caroline A. Austin
MOLECULAR PHARMACOLOGY
(2020)
Article
Chemistry, Medicinal
Anna Jirkovska, Galina Karabanovich, Jan Kubes, Veronika Skalicka, Iuliia Melnikova, Jan Korabecny, Tomas Kucera, Eduard Jirkovsky, Lucie Novakova, Hana Bavlovic Piskackova, Josef Skoda, Martin Sterba, Caroline A. Austin, Tomas Simunek, Jaroslav Roh
Summary: The cardioprotective activity of dexrazoxane analogues is strongly correlated with their interaction with TOP2B in cardiomyocytes, rather than their iron chelation ability. ICRF-193 has been identified as a new lead compound for developing efficient cardioprotective agents, showing better inhibition of TOP2B and higher cardioprotective efficiency compared to dexrazoxane.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Rebecca L. Swan, Ian G. Cowell, Caroline A. Austin
Summary: The study reveals that VCP/p97 plays a role in mediating the proteasomal degradation of TOP2-DNA covalent complexes, potentially important for DSB repair after treatment with TOP2 poisons.
MOLECULAR PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Caroline A. Austin, Ian G. Cowell, Mushtaq M. Khazeem, Dawn Lok, Huei Teng Ng
Summary: Transcription is regulated and mediated by multiprotein complexes in a chromatin context, with DNA topoisomerases playing a crucial role in modulating changes in DNA topology. Lack of DNA topoisomerase II beta (TOP2B) can alter transcription of many genes, particularly long genes. Research has shown interactions of TOP2B with proteins involved in transcription regulation by ligands, chromosome organization, and other key regulators, providing insights into the mechanisms of transcription regulation.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2021)
Article
Allergy
Lori Broderick, Gwendolyn M. Clay, Robert H. Blum, Yang Liu, Rachael McVicar, Fabio Papes, Laela M. Booshehri, Ian G. Cowell, Caroline A. Austin, Christopher D. Putnam, Dan S. Kaufman
Summary: The study examines the impact of Hoffman syndrome-associated mutations in TOP2B on the development and function of NK cells. Using a knockin murine model and patient-derived iPSCs, the researchers investigated NK-cell development in mouse bone marrow and spleen, and assessed the immunophenotype, gene expression, and cytotoxic activity of NK cells in both murine and human models.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2022)
Review
Pharmacology & Pharmacy
Rebecca L. Swan, Ian G. Cowell, Caroline A. Austin
Summary: DNA topoisomerase II regulates DNA topology by introducing enzyme-bridged DNA double-strand breaks. Failure to complete repair of these breaks can be cytotoxic. Understanding the post-translational modifications involved in the repair process may improve the effectiveness of topoisomerase poison chemotherapy.
MOLECULAR PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Elise M. Ling, Arnaud Basle, Ian G. Cowell, Bert van den Berg, Tim R. Blower, Caroline A. Austin
Summary: This study investigates the conformational changes and ATP hydrolysis mechanism of the ATPase domain of human topoisomerase II beta (TOP2B). It reveals that the GHKL domains are similar while the QTK loop can move for product release. Key drug-binding residues and the impact of the N-terminal strap and residue E103 on ATP hydrolysis are also identified.
Article
Neurosciences
Mushtaq M. Khazeem, John W. Casement, George Schlossmacher, Niall S. Kenneth, Nielda K. Sumbung, Janice Yuen Tung Chan, Jade F. McGow, Ian G. Cowell, Caroline A. Austin
Summary: The neuroblastoma cell line SH-SY5Y is a versatile tool for studying gene expression and differentiation. DNA topoisomerase IIB (TOP2B) plays an important role in regulating the phenotype of these cells, promoting the expression of neural-like characteristics and suppressing the mesenchymal transcription program.
MOLECULAR NEUROBIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Ian G. Cowell, Caroline A. Austin
Summary: The MLL/KMT2A gene is frequently rearranged in childhood and adult acute leukaemia and in secondary leukaemias occurring after therapy with DNA topoisomerase targeting anti-cancer agents. Recent studies have shown that etoposide-induced DNA cleavage plays an important role in MLL/KMT2A translocations.
