Article
Biochemistry & Molecular Biology
Antonella Di Mambro, Yoana Arroyo-Berdugo, Tiziana Fioretti, Michael Randles, Luca Cozzuto, Vinothini Rajeeve, Armando Cevenini, Michael J. Austin, Gabriella Esposito, Julia Ponomarenko, Claire M. Lucas, Pedro Cutillas, John Gribben, Owen Williams, Yolanda Calle, Bela Patel, Maria Teresa Esposito
Summary: This study reveals the essential role and underlying mechanisms of the endogenous phosphatase inhibitor SET in KMT2A-rearranged (KMT2A-R) leukemia, and suggests that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.
Article
Cell Biology
Bernd B. Zeisig, Tsz Kan Fung, Magdalena Zarowiecki, Chiou Tsun Tsai, Huacheng Luo, Boban Stanojevic, Claire Lynn, Anskar Y. H. Leung, Jan Zuna, Marketa Zaliova, Martin Bornhauser, Malte von Bonin, Boris Lenhard, Suming Huang, Ghulam J. Mufti, Chi Wai Eric So
Summary: This study identified two distinct origins of human LSCs for MLL-AML and their role in mediating chemoresistance, as well as a potential therapeutic avenue for stem cell-associated treatment resistance by repurposing the well-tolerated antidiarrhea drug fidaxomicin.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Review
Oncology
Tiffany M. Tran, Dinesh S. Rao
Summary: RNA binding proteins (RBPs) have emerged as important regulators of post-transcriptional gene expression, influencing mRNA fate through multiple mechanisms and critically impacting oncogenic transcript expression. This article focuses on the major features and mechanisms of RBPs, and discusses the current progress in investigating the function of important RBPs in MLL-rearranged leukemia.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2022)
Article
Hematology
Milad Rasouli, Helen Blair, Selina Troester, Katarzyna Szoltysek, Rachel Cameron, Minoo Ashtiani, Anja Krippner-Heidenreich, Florian Grebien, Gerard McGeehan, C. Michel Zwaan, Olaf Heidenreich
Summary: Chromosomal translocations involving the NUP98 locus are common in pediatric AML and can be targeted by inhibiting the Menin-MLL interaction. Menin inhibition impairs AML cell proliferation and clonogenicity, promotes myeloid differentiation, reduces the expression of critical NUP98 fusion protein-target genes, and suppresses FLT3 expression.
Article
Hematology
Milad Rasouli, Helen Blair, Selina Troester, Katarzyna Szoltysek, Rachel Cameron, Minoo Ashtiani, Anja Krippner-Heidenreich, Florian Grebien, Gerard McGeehan, C. Michel Zwaan, Olaf Heidenreich
Summary: Chromosomal translocations involving the NUP98 locus are common in pediatric acute myeloid leukemia, leading to overexpression of HOXA and MEIS1 genes and poor clinical outcome. Inhibiting the Menin-MLL interaction can effectively suppress the propagation of NUP98-rearranged AML, impair proliferation, induce myeloid differentiation, and downregulate NUP98 fusion protein-target genes.
Article
Medicine, Research & Experimental
Tiago Oliveira, Mingfeng Zhang, Eun Ji Joo, Hisham Abdel-Azim, Chun-Wei Chen, Lu Yang, Chih-Hsing Chou, Xi Qin, Jianjun Chen, Kathirvel Alagesan, Andreia Almeida, Francis Jacob, Nicolle H. Packer, Mark von Itzstein, Nora Heisterkamp, Daniel Kolarich
Summary: This study integrated transcriptomics, proteomics and glycomics data to reveal extensive remodeling of glycocalyx in MLL-r cells, identifying potential therapeutic targets and previously unknown protein targets. The research demonstrated the importance of a systematic combined multi-omics approach in providing important diagnostic information that may be missed with a single omics technology.
Article
Biochemistry & Molecular Biology
Lulu Liu, Xin Guo, Yao Wang, Guo Li, Yanyan Yu, Yang Song, Chenhui Zeng, Zhilou Ding, Yuanjun Qiu, Feifei Yan, Yi-Xiang Zhang, Caiqi Zhao, Yan Zhang, Yali Dou, Peter Atadja, En Li, He Wang
Summary: WDR5 plays an important role in cancer cells through its interaction with oncogenic genes such as MLL and MYC, making it a promising target for pharmacological inhibition. However, the specific role of WDR5 in cancer cells has not been well understood genetically. This study provides genetic evidence that deletion of the Wdr5 gene impairs cell growth and colony formation, and attenuates leukemogenesis in an MLL-AF9 leukemia model. Pharmacological inhibition of Wdr5 produces similar results. Therefore, this study demonstrates the essential role of Wdr5 in MLL-rearranged leukemia through genetic evidence, supporting the therapeutic targeting of WDR5 in this disease.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Article
Biology
William F. Richter, Rohan N. Shah, Alexander J. Ruthenburg
Summary: Research shows that MLL-rearranged leukemia depends on H3K79 methylation, with depletion of this mark downregulating key genes and alternative proliferation pathways. Low-dose pinometostat specifically targets FLT3 transcription, providing a potential treatment strategy for FLT3-mutant leukemia.
Article
Biochemistry & Molecular Biology
Lulu Liu, Lingling Shen, Zhilou Ding, Miao He, En Li, John A. Tallarico, Rishi K. Jain, He Wang
Summary: Drug resistance is a major problem in targeted cancer therapy that can be caused by mutations or activation of bypass signaling pathways. WDR5 has been identified as a potential drug target due to its multifaceted function in cancer. This study found that cancer cells can develop resistance to a powerful WDR5 inhibitor through a specific mutation, providing insights into the resistance mechanism for future clinical research.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jacqueline Fischer, Estelle Erkner, Rahel Fitzel, Pia Radszuweit, Hildegard Keppeler, Fulya Korkmaz, Giovanni Roti, Claudia Lengerke, Dominik Schneidawind, Corina Schneidawind
Summary: The NOTCH1 pathway plays an important role in the pathogenesis of MLLr leukemia and its inhibition can lead to specific anti-leukemic effects, providing potential for further evaluation in clinical settings.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Xiao-Na Zhu, Yu-Sheng Wei, Qian Yang, Hao-Ran Liu, Zhe Zhi, Di Zhu, Li Xia, Deng-Li Hong, Yun Yu, Guo-Qiang Chen
Summary: In this study, it was found that FBXO22 is highly expressed in MLLr AML and promotes AML progression by targeting BACH1 for degradation. Knockdown of FBXO22 leads to increased apoptosis in MLLr leukemia cells and reduced LSCs in serial transplantations. Targeting FBXO22 could be an ideal strategy to eradicate LSCs without affecting normal hematopoiesis.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)
Review
Oncology
Yan Yi, Shenglei Ge
Summary: This article reviews the recent advances and future trends of therapeutic strategies against DOT1L for MLL-rearranged leukemias, and discusses the limitations, challenges, and prospects of these strategies. DOT1L, as a therapeutic target for MLL-rearranged leukemias, holds important research and development value.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2022)
Article
Medicine, General & Internal
Anne P. de Groot, Yoriko Saito, Eiryo Kawakami, Mari Hashimoto, Yuki Aoki, Rintaro Ono, Ikuko Ogahara, Saera Fujiki, Akiko Kaneko, Kaori Sato, Hiroshi Kajita, Takashi Watanabe, Masatoshi Takagi, Daisuke Tomizawa, Katsuyoshi Koh, Mariko Eguchi, Eiichi Ishii, Osamu Ohara, Leonard D. Shultz, Shuki Mizutani, Fumihiko Ishikawa
Summary: MLL-ALL with MLL gene rearrangement is often resistant to glucocorticoids (GCs). In this study, SFKs and FLT3 signaling pathways were found to be over-represented in MLL-ALL cells. Inhibitors of SFKs/FLT3 were able to eliminate MLL-ALL cells and combined inhibition of these pathways with BCL-2 led to successful elimination of highly resistant MLL-ALL cells. Triple treatment combining GCs, SFKs/FLT3 inhibitors, and BCL-2 inhibitors resulted in complete elimination of MLL-ALL cells in vivo.
Article
Biochemistry & Molecular Biology
Mark Kerstjens, Patricia Garrido Castro, Sandra S. Pinhancos, Pauline Schneider, Priscilla Wander, Rob Pieters, Ronald W. Stam
Summary: Acute lymphoblastic leukemia (ALL) in infants involving MLL gene translocations accounts for about 80% of cases, with poor prognoses under current chemotherapeutic regimens. Through in vitro drug screening, Camptothecin and its derivatives showed potent effects on ALL cell lines. Further study revealed that Irinotecan, a pro-drug of SN-38, exhibited strong anti-leukemia effects against pediatric MLL-rearranged ALL.
Article
Oncology
Wallace Bourgeois, Scott A. Armstrong, Brandon J. Aubrey
Summary: The transcription factor IKAROS plays a crucial role in maintaining leukemogenic gene expression in MLL1-rearranged acute myeloid leukemia, and pharmacological degradation of IKAROS enhances the effectiveness of inhibitors targeting the MLL1-MENIN protein-protein interaction, leading to better disruption of leukemogenic transcriptional networks and improved therapeutic benefits in preclinical models.
Article
Hematology
Desmond Wai Loon Chin, Tetsuichi Yoshizato, Stina Virding Culleton, Francesca Grasso, Magdalena Barbachowska, Seishi Ogawa, Sten Eirik W. Jacobsen, Petter S. Woll
Article
Hematology
Hideki Makishima, Ryunosuke Saiki, Yasuhito Nannya, Sophia Korotev, Carmelo Gurnari, June Takeda, Yukihide Momozawa, Steve Best, Pramila Krishnamurthy, Tetsuichi Yoshizato, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Nobuyuki Kakiuchi, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Ayana Kon, Yotaro Ochi, Masahiro M. Nakagawa, Rurika Okuda, Takuto Mori, Akinori Yoda, Hidehiro Itonaga, Yasushi Miyazaki, Masashi Sanada, Takayuki Ishikawa, Shigeru Chiba, Hisashi Tsurumi, Senji Kasahara, Carsten Mueller-Tidow, Akifumi Takaori-Kondo, Kazuma Ohyashiki, Toru Kiguchi, Fumihiko Matsuda, Joop H. Jansen, Chantana Polprasert, Piers Blombery, Yoichiro Kamatani, Sator Miyano, Luca Malcovati, Torsten Haferlach, Michiaki Kubo, Mario Cazzola, Austin G. Kulasekararaj, Lucy A. Godley, Jaroslaw P. Maclejewski, Seishi Ogawa
Summary: DDX41 gene mutations play an important role in late-onset myeloid neoplasms, but many crucial features of DDX41-mutated neoplasms still need to be elucidated. This study comprehensively characterized DDX41-mutated neoplasms and found that DDX41 risk variants accounted for 80% of known genetic predispositions to myeloid neoplasms in adults. Additionally, DDX41 risk alleles were significantly enriched in Japanese cases and more prominent in males compared to females.
Article
Hematology
Shiho Taniguchi, Sae Utsumi, Yu Kochi, Yuki Taya, Yasuo Mori, Yu-ichiro Semba, Takeshi Sugio, Kohta Miyawaki, Yoshikane Kikushige, Yuya Kunisaki, Goichi Yoshimoto, Akihiko Numata, Koji Kato, Naoyuki Uchida, Takahiro Maeda, Toshihiro Miyamoto, Shuichi Taniguchi, Koichi Akashi
Summary: Donor-derived hematological malignancies are rare but serious complications in allo-HSCT recipients. We report a case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT. The patient remained disease-free after intensive chemotherapy and stem cell transplantation.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Letter
Oncology
Shunsuke Yamamoto, Shingo Nakao, Hirosuke Inoue, Yuhki Koga, Kanako Kojima-Ishii, Yuichiro Semba, Takahiro Maeda, Koichi Akashi, Shouichi Ohga
PEDIATRIC BLOOD & CANCER
(2023)
Article
Hematology
Yotaro Ochi
Summary: This review summarizes the genetic abnormalities in chronic myeloid leukemia (CML) and discusses their clinical impact on disease subtypes, drug resistance, and prognosis.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Article
Oncology
Michitaka Nakano, Ryosuke Taguchi, Yoshikane Kikushige, Taichi Isobe, Kohta Miyawaki, Shinichi Mizuno, Nobuhiro Tsuruta, Fumiyasu Hanamura, Kyoko Yamaguchi, Takuji Yamauchi, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Calvin J. Kuo, Eishi Baba, Koichi Akashi
Summary: The identification of molecules that characterize cancer stem cells (CSCs) is crucial for understanding tumor heterogeneity and developing new therapeutic strategies. However, conventional markers are still insufficient for isolating CSCs. In this study, we investigated organoids, miniature tumor tissues, to identify specific markers for CSCs. We found that the receptor for hyaluronan-mediated motility (RHAMM) expressed in a subpopulation of CD44+ colorectal CSCs. Inhibition of RHAMM strongly suppressed tumor growth, suggesting it as a potential therapeutic target.
Article
Biochemistry & Molecular Biology
Yuichi Shiraishi, Junji Koya, Kenichi Chiba, Ai Okada, Yasuhito Arai, Yuki Saito, Tatsuhiro Shibata, Keisuke Kataoka
Summary: We introduce nanomonsv, a novel software for detecting somatic structural variations (SVs) using tumor and matched control long-read sequencing data with single-base resolution. It includes two detection modules: Canonical SV module and Single breakend SV module. Our approaches demonstrate higher precision and recall in identifying somatic SVs compared to existing methods, and enable the classification and analysis of various features of SVs, providing insights into mutational processes and functional consequences.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Yosuke Komata, Akinori Kanai, Takahiro Maeda, Toshiya Inaba, Akihiko Yokoyama
Summary: Changes in transcriptional machinery cause abnormal self-renewal of non-stem hematopoietic progenitors. AF10 fusion proteins, like CALM-AF10, are generated through chromosomal translocation and induce malignant leukemia. This study demonstrates that AF10 fusion proteins trigger abnormal self-renewal through ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction between ENL and MOZ, mediated by its YEATS domain, is crucial for CALM-AF10-induced leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention through KAT activity, suggesting that inhibiting MOZ/MORF KATs directly suppresses the function of AF10 fusion proteins and exhibits strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L promotes differentiation of CALM-AF10-leukemia cells. These findings highlight the importance of the MOZ/ENL complex in recruiting the AF10 fusion/DOT1L complex and provide a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia.
NATURE COMMUNICATIONS
(2023)
Article
Hematology
Yuichi Horigome, Masaki Iino, Yoriko Harazaki, Takahiro Kobayashi, Hiroshi Handa, Yasushi Hiramatsu, Taiga Kuroi, Kazuki Tanimoto, Kosei Matsue, Masahiro Abe, Tadao Ishida, Shigeki Ito, Hiromi Iwasaki, Junya Kuroda, Hirohiko Shibayama, Kazutaka Sunami, Hiroyuki Takamatsu, Hideto Tamura, Toshiaki Hayashi, Kiwamu Akagi, Takahiro Maeda, Takahiro Yoshida, Ikuo Mori, Tomohiro Shinozaki, Shinsuke Iida
Summary: This study investigated the effectiveness and safety of Ixazomib plus Lenalidomide and Dexamethasone (IRd) in real-world clinical practice for 295 patients with relapsed/refractory multiple myeloma (RRMM) in Japan. The results showed that IRd regimen was effective and well-tolerated, providing a viable treatment option for RRMM patients.
ANNALS OF HEMATOLOGY
(2023)
Editorial Material
Hematology
Takahiro Maeda
Article
Multidisciplinary Sciences
Tomomi Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida, Takaki Sakurai, Tatsuki R. R. Kataoka, Eiji Kondoh, Yoshitsugu Chigusa, Masahiko Kawai, Morio Sawada, Takuya Inoue, Yasuhide Takeuchi, Hirona Maeda, Satoko Baba, Yusuke Shiozawa, Ryunosuke Saiki, Masahiro M. M. Nakagawa, Yasuhito Nannya, Yotaro Ochi, Tomonori Hirano, Tomoe Nakagawa, Yukiko Inagaki-Kawata, Kosuke Aoki, Masahiro Hirata, Kosaku Nanki, Mami Matano, Megumu Saito, Eiji Suzuki, Masahiro Takada, Masahiro Kawashima, Kosuke Kawaguchi, Kenichi Chiba, Yuichi Shiraishi, Junko Takita, Satoru Miyano, Masaki Mandai, Toshiro Sato, Kengo Takeuchi, Hironori Haga, Masakazu Toi, Seishi Ogawa
Summary: Recent studies have shown that clones carrying common cancer mutations frequently evolve in normal tissues, but we still lack knowledge about the additional driver events that occur before these clones evolve into cancer. In this study, using phylogenetic analyses, we found unique evolutionary histories in breast cancers with der(1;16), a common driver alteration. The timing of early evolutionary events was estimated and showed that both cancer and non-cancer clones evolved from a common ancestor in the patient's early 30s. Multiple independent cancer founders from non-cancer ancestors were also observed, contributing to intratumor heterogeneity. These findings provide new insights into the evolution of breast cancer.
Article
Oncology
Eirini Giannakopoulou, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Yingqian Li, Terhi Karpanen, Tetsuichi Yoshizato, Even H. Rustad, Morten Milek Nielsen, Ravi Chand Bollineni, Trung T. Tran, Marina Delic-Sarac, Thea Johanne Gjerdingen, Karolos Douvlataniotis, Maarja Laos, Muhammad Ali, Amy Hillen, Stefania Mazzi, Desmond Wai Loon Chin, Adi Mehta, Jeppe Sejero Holm, Amalie Kai Bentzen, Marie Bill, Marieke Griffioen, Tobias Gedde-Dahl, Soren Lehmann, Sten Eirik W. Jacobsen, Petter S. Woll, Johanna Olweus
Summary: The study identifies a T cell receptor reactive against a driver mutation in FLT3 in acute myeloid leukemia and demonstrates the efficacy of engineered T cells against this mutation in immunotherapy.
Article
Oncology
Asami Yamada, Jun-ichirou Yasunaga, Lihan Liang, Wenyi Zhang, Junya Sunagawa, Shinji Nakaoka, Shingo Iwami, Yasunori Kogure, Yuta Ito, Keisuke Kataoka, Masanori Nakagawa, Masako Iwanaga, Atae Utsunomiya, Ki-Ryang Koh, Toshiki Watanabe, Kisato Nosaka, Masao Matsuoka
Summary: This study demonstrates that profiling the humoral immunity to HTLV-1 antigens and measuring proviral load can be used to classify disease status and predict the development of HTLV-1-associated diseases. The study also highlights the importance of anti-Gag proteins in disease prognosis.
Meeting Abstract
Oncology
June Takeda, Kenichi Yoshida, Akinori Yoda, Yasuhito Nannya, Yotaro Ochi, Masahiro Nakagawa, Ryunosuke Saiki, Yuichi Shiraishi, Yasunobu Nagata, Akifumi Takaori, Shigeru Chiba, Keisuke Kataoka, Satoru Miyano, Hideki Makishima, Seishi Ogawa