Article
Hematology
Tomofumi Yamamoto, Jun Nakayama, Yusuke Yamamoto, Masahiko Kuroda, Yutaka Hattori, Takahiro Ochiya
Summary: This study reveals the molecular and cellular mechanisms of lenalidomide resistance in multiple myeloma (MM), showing that lenalidomide-resistant MM cells have enhanced extracellular vesicle (EV) secretion and adherence abilities. SORT1 and LAMP2 genes are identified as key regulators of EV secretion. Silencing of these genes decreases EV secretion and impairs cell adhesion in resistant cells, resulting in increased sensitivity to lenalidomide. Analysis of transcriptome data supports the relationship between genes related to EV secretion and adherence and patient prognosis.
Article
Oncology
Laure Maneix, Melanie A. Sweeney, Sukyeong Lee, Polina Iakova, Shannon E. Moree, Ergun Sahin, Premal Lulla, Sarvari V. Yellapragada, Francis T. F. Tsai, Andre Catic
Summary: Multiple myeloma is the second most common cancer of the blood system in the US, with no effective cure currently available. The study shows that overexpression of the mitochondrial matrix protease LonP1 reduces the efficacy of proteasome inhibitors, potentially leading to drug resistance in multiple myeloma. Targeting both the proteasome and mitochondrial proteases like LonP1 could be beneficial for the treatment of this incurable cancer.
Article
Multidisciplinary Sciences
Jing Liu, Ying Xie, Jing Guo, Xin Li, Jingjing Wang, Hongmei Jiang, Ziyi Peng, Jingya Wang, Sheng Wang, Qian Li, Linquan Ye, Yuping Zhong, Qiguo Zhang, Xiaozhi Liu, David M. Lonard, Jin Wang, Bert W. O'Malley, Zhiqiang Liu
Summary: High expression of steroid receptor coactivator-3 (SRC-3) is correlated with relapse/refractory and poor outcomes in multiple myeloma (MM) patients treated with bortezomib (BTZ)-based regimens, and overexpression of histone methyltransferase NSD2 may contribute to acquired drug resistance by coordinating and enhancing SRC-3 in MM cells. Targeting SRC-3 or interfering with its interactions with NSD2 using a newly developed inhibitor, SI-2, can sensitize BTZ treatment and overcome drug resistance in MM patients.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Odai Darawshi, Barbara Muz, Shiri Gershon Naamat, Bellam Praveen, Mohamed Mahameed, Karin Goldberg, Priya Dipta, Miriam Shmuel, Francesca Forno, Shatha Boukeileh, Hadas Pahima, Julia Hermann, Marc S. Raab, Alexandra M. Poos, Niels Weinhold, Chaggai Rosenbluh, Moshe E. Gatt, Wilhelm Palm, Abdel Kareem Azab, Boaz Tirosh
Summary: The study found that inactivation of mTORC1 is an intrinsic response of multiple myeloma to proteasome inhibitors. Genetically enforced hyperactivation of mTORC1 in multiple myeloma compromised tumorigenicity in mice and increased sensitivity to proteasome inhibitors and hypoxia in vitro.
CELL DEATH & DISEASE
(2022)
Article
Hematology
Jingyu Zhang, Fangming Shi, Xing Liu, Xuan Wu, Cong Hu, Jiaojiao Guo, Qin Yang, Jiliang Xia, Yanjuan He, Gang An, Lugui Qiu, Xiangling Feng, Wen Zhou
Summary: Amino acids, particularly proline, in the bone marrow microenvironment (BMME) play a crucial role in multiple myeloma (MM) progression. Elevated proline levels in BMME are associated with poor prognosis in MM patients. The abnormal expression of proline dehydrogenase (PRODH), a key enzyme in proline catabolism, and bone collagen degradation contribute to the increased proline levels. PRODH downregulation in MM patients is mainly caused by promoter hypermethylation and overexpression of DNMT3b. Overexpression of PRODH suppresses MM cell proliferation and drug resistance, suggesting its potential as a therapeutic target for MM treatment.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Hamed Bashiri, Hossein Tabatabaeian
Summary: Multiple myeloma, the second most prevalent hematologic malignancy, has seen increased survival rates due to novel drugs and combination therapies. However, drug resistance remains a significant issue, with autophagic activity playing a critical role. High mobility group box protein 1 (HMGB1)-dependent autophagy and proteasome suppression-induced autophagy have been found to contribute to drug resistance in multiple myeloma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biotechnology & Applied Microbiology
Dan Chen, Xinhong Yang, Min Liu, Zhihua Zhang, Enhong Xing
Summary: miRNAs play a critical role in regulating pathological factors involved in the progression of multiple myeloma, including bone marrow microenvironment, methylation, immune regulation, genomic instability, and drug resistance. They also have potential as novel prognostic biomarkers and therapeutic targets.
CANCER GENE THERAPY
(2021)
Article
Medicine, Research & Experimental
Lina Quan, Chuiming Jia, Yiwei Guo, Yao Chen, Xinya Wang, Qiuting Xu, Yu Zhang
Summary: This study investigates the methylation pattern of multiple myeloma and its effect on the expression of HNRNPA2B1 and downstream targets. The findings suggest that HNRNPA2B1 increases cell proliferation and deregulates cell apoptosis in multiple myeloma through TLR4 signaling.
JOURNAL OF TRANSLATIONAL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Max Von Suskil, Kazi Nasrin Sultana, Weam Othman Elbezanti, Omar S. Al-Odat, Robert Chitren, Amit K. Tiwari, Kishore B. Challagundla, Sandeep Kumar Srivastava, Subash C. Jonnalagadda, Tulin Budak-Alpdogan, Manoj K. Pandey
Summary: Multiple myeloma remains an incurable disease despite advancements in treatment, leading to aggressive relapses in patients. The cytosolic kinase BTK plays a crucial role in the survival of malignant clones and multiple myeloma stem cells, making it a promising therapeutic target. Inhibition of the BTK pathway may disrupt interactions between malignant clones and the bone marrow microenvironment in MM patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Chemistry, Medicinal
Guoyuan Tang, Shan Huang, Ji Luo, Yingmiao Wu, Shuai Zheng, Rongsheng Tong, Ling Zhong, Jianyou Shi
Summary: This review article summarizes the characteristics, clinical investigations, and future development directions of multiple myeloma drugs, including their structures, mechanisms of action, clinical study progress, and the potential applications of drugs that have not yet entered clinical trials.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Chunsheng Zhu, Aoxiang Guo, Bao Sun, Zheng Zhou
Summary: This review comprehensively elaborates on the role of circular RNAs in multiple myeloma (MM), highlighting their potential as biomarkers in diagnosis and therapy.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Cell Biology
Shamila D. Alipoor, Hong Chang
Summary: Multiple myeloma (MM) is a malignancy of plasma cells in the bone marrow characterized by the clonal proliferation of B-cells producing defective monoclonal immunoglobulins. Drug resistance remains a major challenge in MM therapy and is influenced by the crosstalk between MM cells and the bone marrow microenvironment (BME). Exosomal miRNAs play a crucial role in this communication, affecting the developmental trajectory and prognosis of MM.
Review
Biochemistry & Molecular Biology
Ilaria Saltarella, Concetta Altamura, Aurelia Lamanuzzi, Benedetta Apollonio, Angelo Vacca, Maria Antonia Frassanito, Jean-Francois Desaphy
Summary: Ion channels play a critical role in multiple myeloma by modulating intracellular pathways that promote tumor cell survival, proliferation, and drug resistance, making them a potential therapeutic target for MM treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Xiang-jin Zheng, Wan Li, Jie Yi, Jin-yi Liu, Li-wen Ren, Xiao-ming Zhu, Shi-wei Liu, Jin-hua Wang, Guan-hua Du
Summary: This study identified high expression of FOXC1 in TNBC, which was associated with overall survival (OS) of patients and inversely correlated with H3K27me3 levels. Inhibition of EZH2 increased FOXC1 expression, which was also linked to doxorubicin resistance in breast cancer cells. This suggests that FOXC1 may serve as a potential biomarker or drug target for TNBCs, and downregulation of FOXC1 could be therapeutically valuable in TNBC treatment.
ACTA PHARMACOLOGICA SINICA
(2021)
Review
Cell Biology
Vanessa Innao, Vincenzo Rizzo, Andrea Gaetano Allegra, Caterina Musolino, Alessandro Allegra
Summary: Multiple myeloma cells acquire drug resistance through reprogramming their metabolic assessment via mitochondrial pathways. Some compounds, such as 2-methoxyestradiol and Artesunate, overcome resistance by increasing oxidative stress, while others restore efficacy through caspase-dependent tools. Each substance improves efficacy rates when used in combination with commonly used antimyeloma drugs.
Article
Oncology
Shiori Saito, Jiro Kikuchi, Daisuke Koyama, Shin Sato, Hiroo Koyama, Naoki Osada, Yoshiaki Kuroda, Koshi Akahane, Takeshi Inukai, Takashi Umehara, Yusuke Furukawa
CLINICAL CANCER RESEARCH
(2019)
Article
Oncology
Jiro Kikuchi, Mitsuo Hori, Hidekatsu Iha, Noriko Toyama-Sorimachi, Shotaro Hagiwara, Yoshiaki Kuroda, Daisuke Koyama, Tohru Izumi, Hiroshi Yasui, Atsushi Suzuki, Yusuke Furukawa
Letter
Hematology
Akiko Nagamachi, Jiro Kikuchi, Akinori Kanai, Yusuke Furukawa, Toshiya Inaba
Article
Medicine, General & Internal
Shogo Yamamoto, Daisuke Koyama, Ryo Igarashi, Takumi Maki, Hiroyuki Mizuno, Yusuke Furukawa, Makoto Kuro-o
Article
Hematology
Yusuke Furukawa, Jiro Kikuchi
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2020)
Letter
Oncology
Atsushi Suzuki, Satoshi Kakugawa, Masafumi Miyoshi, Mitsuo Hori, Kenshi Suzuki, Yusuke Furukawa, Kensuke Ohta
Article
Multidisciplinary Sciences
Junya Tamaoki, Miki Takeuchi, Ryo Abe, Hiroshi Kaneko, Taeko Wada, Shinjiro Hino, Mitsuyoshi Nakao, Yusuke Furukawa, Makoto Kobayashi
SCIENTIFIC REPORTS
(2020)
Article
Oncology
Daisuke Koyama, Jiro Kikuchi, Yoshiaki Kuroda, Masatsugu Ohta, Yusuke Furukawa
Summary: This study reveals the critical role of metabolic homeostasis in the survival of CML cells, particularly in advanced stages of the disease. The BCR-ABL protein activates AMP-activated protein kinase and the mTOR pathway to regulate ATP production and autophagy, with nuclear BCR-ABL detected in advanced-stage CML cells. Activation of AMPK triggers autophagy under energy-deprived conditions, leading to cytoplasmic translocation of BCR-ABL and eventual apoptotic cell death when intracellular ATP is exhausted. This pathway represents a novel therapeutic vulnerability for treating TKI-resistant CML.
Letter
Oncology
Yoshiaki Kuroda, Akiko Yashima-Abo, Daisuke Koyama, Jiro Kikuchi, Shigehisa Mori, Shigeki Ito, Yusuke Furukawa
Article
Cell Biology
Koji Funato, Takaaki Abe, Ryo Kurita, Yoshihisa Watanabe, Yukio Nakamura, Shigeki Miyata, Yusuke Furukawa, Masahiro Satake
Summary: The production of red blood cells in vitro has been improved for basic or clinical research purposes. The study identified proteins showing reproducible differential expression during erythroid differentiation and found that most early-stage proteins were downregulated, while seven proteins showed upregulated expression in both bone marrow and cord blood cells. The roles of these proteins in erythropoiesis require further clarification, as they may contribute to erythroid differentiation.
Letter
Hematology
Naoki Osada, Jiro Kikuchi, Daisuke Koyama, Yoshiaki Kuroda, Hiroshi Yasui, Joel D. Leverson, Yusuke Furukawa
Article
Oncology
Yoshiaki Kuroda, Daisuke Koyama, Jiro Kikuchi, Shigehisa Mori, Tatsuo Ichinohe, Yusuke Furukawa
Summary: MCL cells develop resistance to bortezomib through autophagic degradation of the pro-apoptotic protein NOXA in the tumor microenvironment. Interaction with stromal cells enhances the ubiquitination and subsequent degradation of NOXA, while stromal-derived factors like interleukin-6 promote selective autophagy. Targeting protective autophagy, such as with lysosome inhibitors like chloroquine, may improve the efficacy of bortezomib-containing regimens in MCL.
Article
Multidisciplinary Sciences
Kenji Tago, Satoshi Ohta, Chihiro Aoki-Ohmura, Megumi Funakoshi-Tago, Miho Sashikawa, Takeshi Matsui, Yuki Miyamoto, Taeko Wada, Tomoyuki Oshio, Mayumi Komine, Jitsuhiro Matsugi, Yusuke Furukawa, Mamitaro Ohtsuki, Junji Yamauchi, Ken Yanagisawa
Summary: NKIRAS1 and NKIRAS2 were identified as atypical RAS family members that may act as tumor suppressors in some contexts, but as necessary factors in oncogenic transformation in other situations. The expression levels of NKIRAS likely determine its functional role in carcinogenesis.
SCIENTIFIC REPORTS
(2021)
Article
Hematology
Jiro Kikuchi, Nobuyuki Kodama, Masataka Takeshita, Sho Ikeda, Takahiro Kobayashi, Yoshiaki Kuroda, Michihiro Uchiyama, Naoki Osada, Bjarne Bogen, Hiroshi Yasui, Naoto Takahashi, Akiyoshi Miwa, Yusuke Furukawa
Summary: Extramedullary disease (EMD) in multiple myeloma (MM) is associated with resistance to chemotherapy and poor prognosis, and its development mechanisms are not fully understood. This study demonstrates that bone marrow stroma cell-derived hyaluronan (HA) binds to surface CD44 on MM cells, leading to the formation of cell clusters that could develop into EMD. These HA-induced cell clusters exhibit resistance to proteasome inhibitors (PIs) through gamma-secretase-mediated cleavage of CD44, and targeting the HA-CD44 axis effectively suppresses EMD development and overcomes PI resistance.
Article
Oncology
Naoki Osada, Jiro Kikuchi, Hidekatsu Iha, Hiroshi Yasui, Sho Ikeda, Naoto Takahashi, Yusuke Furukawa
Summary: The immunomodulatory drug lenalidomide exerts its pharmacological action in multiple myeloma cells through the degradation of IKZF1 and down-regulation of IRF4. A study found that c-FOS, a member of the AP-1 family, is an integral component of the IKZF1 complex and is responsible for its activator function in MM cells. Inhibiting c-FOS enhances the anti-MM activity of lenalidomide and mitigates drug resistance.
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)