PMID- 34088671
OWN - NLM
STAT- MEDLINE
DCOM- 20220408
LR  - 20220408
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 7
IP  - 23
DP  - 2021 Jun
TI  - ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow 
      microenvironment.
LID - 10.1126/sciadv.abg2697 [doi]
LID - eabg2697
AB  - Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple 
      myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. 
      Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 
      (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via 
      activation of noncanonical nuclear factor kappaB (NF-kappaB) and extracellular 
      signal-regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell 
      supernatants, TNF-alpha induces proteasomal degradation of TRAF2, noncanonical NF-kappaB, 
      and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers 
      ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK 
      pathway activation at relapse on lenalidomide maintenance therapy, confirming its 
      clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity 
      of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework 
      for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM 
      microenvironment and improve patient outcome in MM.
CI  - Copyright (c) 2021 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 
      (CC BY-NC).
FAU - Liu, Jiye
AU  - Liu J
AUID- ORCID: 0000-0001-7970-7508
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
FAU - Hideshima, Teru
AU  - Hideshima T
AUID- ORCID: 0000-0003-2939-6224
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
FAU - Xing, Lijie
AU  - Xing L
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
AD  - Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong 
      First Medical University, Jinan, Shandong 250021, China.
FAU - Wang, Su
AU  - Wang S
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, 
      USA.
FAU - Zhou, Wenrong
AU  - Zhou W
AD  - Oncology and Immunology Unit, Research Service Division, WuXi AppTec (Shanghai) 
      Co., Ltd., Shanghai 200131, China.
FAU - Samur, Mehmet K
AU  - Samur MK
AUID- ORCID: 0000-0002-9978-5682
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
AD  - Department of Biostatistics and Computational Biology, Harvard T.H. Chan School 
      of Public Health, Boston, 02115 MA, USA.
FAU - Sewastianik, Tomasz
AU  - Sewastianik T
AUID- ORCID: 0000-0003-4603-8517
AD  - Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Department of Experimental Hematology, Institute of Hematology and Transfusion 
      Medicine, Warsaw 02776, Poland.
FAU - Ogiya, Daisuke
AU  - Ogiya D
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
FAU - An, Gang
AU  - An G
AD  - State Key Laboratory of Experimental Hematology, Institute of Hematology and 
      Blood Diseases Hospital, Chinese Academy of Medical Science and Peking Union 
      Medical College, Tianjin 300020, China.
FAU - Gao, Shaobing
AU  - Gao S
AUID- ORCID: 0000-0002-8307-9281
AD  - The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
FAU - Yang, Li
AU  - Yang L
AD  - Multiple Myeloma Treatment Center and Bone Marrow Transplantation Center, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 
      310003, China.
FAU - Ji, Tong
AU  - Ji T
AD  - Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University 
      School of Medicine, Hangzhou 310020, China.
FAU - Bianchi, Giada
AU  - Bianchi G
AD  - Division of Hematology, Department of Internal Medicine, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Wen, Kenneth
AU  - Wen K
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
FAU - Tai, Yu-Tzu
AU  - Tai YT
AUID- ORCID: 0000-0001-6199-3569
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
FAU - Munshi, Nikhil
AU  - Munshi N
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
FAU - Richardson, Paul
AU  - Richardson P
AUID- ORCID: 0000-0002-7426-8865
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
FAU - Carrasco, Ruben
AU  - Carrasco R
AD  - Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02115, USA.
FAU - Cang, Yong
AU  - Cang Y
AUID- ORCID: 0000-0002-1148-7008
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, 
      China.
FAU - Anderson, Kenneth C
AU  - Anderson KC
AUID- ORCID: 0000-0002-6418-0886
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. 
      kenneth_anderson@dfci.harvard.edu.
LA  - eng
GR  - P50 CA100707/CA/NCI NIH HHS/United States
GR  - R01 CA050947/CA/NCI NIH HHS/United States
GR  - R01 CA178264/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210604
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
RN  - 0 (Immunomodulating Agents)
RN  - 0 (NF-kappa B)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Bone Marrow/pathology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - *Immunomodulating Agents
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism/therapeutic use
MH  - *Multiple Myeloma/drug therapy/genetics/metabolism
MH  - NF-kappa B/metabolism
MH  - Neoplasm Recurrence, Local
MH  - TNF Receptor-Associated Factor 2/metabolism
MH  - Tumor Microenvironment
PMC - PMC8177702
EDAT- 2021/06/06 06:00
MHDA- 2022/04/09 06:00
PMCR- 2021/06/04
CRDT- 2021/06/05 05:34
PHST- 2020/12/21 00:00 [received]
PHST- 2021/04/19 00:00 [accepted]
PHST- 2021/06/05 05:34 [entrez]
PHST- 2021/06/06 06:00 [pubmed]
PHST- 2022/04/09 06:00 [medline]
PHST- 2021/06/04 00:00 [pmc-release]
AID - 7/23/eabg2697 [pii]
AID - abg2697 [pii]
AID - 10.1126/sciadv.abg2697 [doi]
PST - epublish
SO  - Sci Adv. 2021 Jun 4;7(23):eabg2697. doi: 10.1126/sciadv.abg2697. Print 2021 Jun.