机构：[1]Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA[2]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA[3]Department of Oncology, Fu Xing Hospital, Capital Medical University, Beijing 100038, China[4]College of Food Science and Technology, Agricultural University of Hebei, Baoding, Hebei 071000, China[5]Department of Ultrasound, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China医技科室超声科河北医科大学第四医院[6]Department of Pathology, Norman Bethune International Peace Hospital, Shijiazhuang, Hebei 050082, China[7]Department of Laboratory Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA[8]Department of Translational Hematology & Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved long non-coding RNA (lncRNA). Overexpression of MALAT1 has been demonstrated to related to poor prognosis of multiple myeloma (MM) patients. Here, we demonstrated that MALAT1 plays important roles in MM DNA repair and cell death. We found bone marrow plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM express elevated MALAT1 and involve in alternative non-homozygous end joining (A-NHEJ) pathway by binding to PARP1 and LIG3, two key components of the A-NHEJ protein complex. Degradation of the MALAT1 RNA by RNase H using antisense gapmer DNA oligos in MM cells stimulated poly-ADP-ribosylation of nuclear proteins, defected the DNA repair pathway, and further provoked apoptotic pathways. Anti-MALAT1 therapy combined with PARP1 inhibitor or proteasome inhibitor in MM cells showed a synergistic effect in vitro. Furthermore, using novel single-wall carbon nanotube (SWCNT) conjugated with anti-MALAT1 oligos, we successfully knocked-down MALAT1 RNA in cultured MM cell lines and xenograft murine models. Most importantly, anti-MALAT1 therapy induced DNA damage and cell apoptosis in vivo, indicating that MALAT1 could serve as a potential novel therapeutic target for MM treatment.
基金：
NIH/NCI grant R00
CA172292 (to J.-J.Z.) and start-up funds (to J.-J.Z.) and the Clinical
and Translational Science Collaborative (CTSC) of Case Western
Reserve University Core Utilization Pilot Grant (to J.-J.Z.). The
Orbitrap Elite instrument was purchased via an NIH shared instrument
grant, 1S10RR031537-01. This work utilized the Leica SP8 confocal
microscope that was purchased with funding from National Institutes
of Health SIG grant 1S10OD019972-01.
第一作者机构：[1]Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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通讯作者：
推荐引用方式(GB/T 7714)：
Hu Yi,Lin Jianhong,Fang Hua,et al.Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma[J].LEUKEMIA.2018,32(10):2250-2262.doi:10.1038/s41375-018-0104-2.
APA：
Hu, Yi,Lin, Jianhong,Fang, Hua,Fang, Jing,Li, Chen...&Zhao, Jian-Jun.(2018).Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma.LEUKEMIA,32,(10)
MLA：
Hu, Yi,et al."Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma".LEUKEMIA 32..10(2018):2250-2262
医学