PMID- 32724061
OWN - NLM
STAT- MEDLINE
DCOM- 20210322
LR  - 20210322
IS  - 2044-5385 (Electronic)
IS  - 2044-5385 (Linking)
VI  - 10
IP  - 7
DP  - 2020 Jul 28
TI  - In vitro and ex vivo gene expression profiling reveals differential kinetic 
      response of HSPs and UPR genes is associated with PI resistance in multiple 
      myeloma.
PG  - 78
LID - 10.1038/s41408-020-00344-9 [doi]
LID - 78
AB  - Extensive inter-individual variation in response to chemotherapy (sensitive vs 
      resistant tumors) is a serious cause of concern in the treatment of multiple 
      myeloma (MM). In this study, we used human myeloma cell lines (HMCLs), and 
      patient-derived CD138+ cells to compare kinetic changes in gene expression 
      patterns between innate proteasome inhibitor (PI)-sensitive and PI-resistant 
      HMCLs following test dosing with the second-generation PI Ixazomib. We found 1553 
      genes that changed significantly post treatment in PI-sensitive HMCLs compared 
      with only seven in PI-resistant HMCLs (p < 0.05). Genes that were uniquely 
      regulated in PI-resistant lines were RICTOR (activated), HNF4A, miR-16-5p 
      (activated), MYCN (inhibited), and MYC (inhibited). Ingenuity pathway analysis 
      (IPA) using top kinetic response genes identified the proteasome ubiquitination 
      pathway (PUP), and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated 
      oxidative stress response as top canonical pathways in Ix-sensitive cell lines 
      and patient-derived cells, whereas EIF2 signaling and mTOR signaling pathways 
      were unique to PI resistance. Further, 10 genes were common between our in vitro 
      and ex vivo post-treatment kinetic PI response profiles and Shaughnessy's 
      GEP80-postBz gene expression signature, including the high-risk PUP gene PSMD4. 
      Notably, we found that heat shock proteins and PUP pathway genes showed 
      significant higher upregulation in Ix-sensitive lines compared with the 
      fold-change in Ix-resistant myelomas.
FAU - Mitra, Amit Kumar
AU  - Mitra AK
AUID- ORCID: 0000-0003-4046-7070
AD  - Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn 
      University, Auburn, AL, USA.
AD  - Department of Genetics, Cell Biology & Development, University of Minnesota, 
      Minneapolis, MN, USA.
AD  - Center for Pharmacogenomics and Single-Cell Omics initiative (AUPharmGx), 
      Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
FAU - Kumar, Harish
AU  - Kumar H
AD  - Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn 
      University, Auburn, AL, USA.
FAU - Ramakrishnan, Vijay
AU  - Ramakrishnan V
AD  - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, 
      MN, USA.
FAU - Chen, Li
AU  - Chen L
AUID- ORCID: 0000-0001-9372-5606
AD  - Division of Hematology/Oncology, School of Medicine, Indiana University, 
      Indianapolis, IN, USA.
FAU - Baughn, Linda
AU  - Baughn L
AD  - Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, 
      Mayo Clinic, Rochester, MN, USA.
FAU - Kumar, Shaji
AU  - Kumar S
AUID- ORCID: 0000-0001-5392-9284
AD  - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, 
      MN, USA.
FAU - Rajkumar, S Vincent
AU  - Rajkumar SV
AUID- ORCID: 0000-0002-5862-1833
AD  - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, 
      MN, USA.
FAU - Van Ness, Brian G
AU  - Van Ness BG
AUID- ORCID: 0000-0003-4985-2274
AD  - Department of Genetics, Cell Biology & Development, University of Minnesota, 
      Minneapolis, MN, USA. vanne001@umn.edu.
LA  - eng
GR  - P50 CA186781/CA/NCI NIH HHS/United States
GR  - U54 CA224018/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 - 20200728
PL  - United States
TA  - Blood Cancer J
JT  - Blood cancer journal
JID - 101568469
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Proteasome Inhibitors)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Biomarkers, Tumor
MH  - Computational Biology
MH  - Drug Resistance, Neoplasm/*genetics
MH  - *Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Heat-Shock Proteins/*genetics
MH  - Humans
MH  - Multiple Myeloma/drug therapy/*genetics/pathology
MH  - Prognosis
MH  - Proteasome Inhibitors/*pharmacology/therapeutic use
MH  - Transcriptome
MH  - Unfolded Protein Response/*genetics
PMC - PMC7387444
COIS- The authors declare that they have no conflict of interest.
EDAT- 2020/07/30 06:00
MHDA- 2021/03/23 06:00
PMCR- 2020/07/28
CRDT- 2020/07/30 06:00
PHST- 2020/04/08 00:00 [received]
PHST- 2020/05/21 00:00 [accepted]
PHST- 2020/05/16 00:00 [revised]
PHST- 2020/07/30 06:00 [entrez]
PHST- 2020/07/30 06:00 [pubmed]
PHST- 2021/03/23 06:00 [medline]
PHST- 2020/07/28 00:00 [pmc-release]
AID - 10.1038/s41408-020-00344-9 [pii]
AID - 344 [pii]
AID - 10.1038/s41408-020-00344-9 [doi]
PST - epublish
SO  - Blood Cancer J. 2020 Jul 28;10(7):78. doi: 10.1038/s41408-020-00344-9.