PMID- 32238854
OWN - NLM
STAT- MEDLINE
DCOM- 20210113
LR  - 20210604
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 35
IP  - 1
DP  - 2021 Jan
TI  - Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent 
      pathways.
PG  - 177-188
LID - 10.1038/s41375-020-0809-x [doi]
AB  - Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide show remarkable 
      antitumor activity in multiple myeloma (MM) via directly inhibiting MM-cell 
      growth in the bone marrow (BM) microenvironment and promoting immune effector 
      cell function. They are known to bind to the ubiquitin 3 ligase CRBN complex and 
      thereby triggering degradation of IKZF1/3. In this study, we demonstrate that 
      IMiDs also directly bind and activate zeta-chain-associated protein kinase-70 
      (Zap-70) via its tyrosine residue phosphorylation in T cells. IMiDs also 
      triggered phosphorylation of Zap-70 in natural killer (NK) cells. Importantly, 
      increased granzyme-B (GZM-B) expression and NK-cell activity triggered by IMiDs 
      is associated with Zap-70 activation and inhibited by Zap-70 knockdown (KD), 
      independent of CRBN. We also demonstrate a second mechanism whereby IMiDs trigger 
      GZM-B and NK cytotoxicity which is CRBN and IKZF3 mediated, and inhibited or 
      enhanced by KD of CRBN or IKZF3, respectively, independent of Zap-70. Our studies 
      therefore show that IMiDs can enhance NK and T-cell cytotoxicity in (1) 
      ZAP-70-mediated CRBN independent, as well as (2) CRBN-mediated ZAP-70 independent 
      mechanisms; and provide the framework for developing novel therapeutics to 
      activate Zap-70 and thereby enhance T and NK anti-MM cytotoxicity.
FAU - Hideshima, Teru
AU  - Hideshima T
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
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 - Liu, Jiye
AU  - Liu J
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
FAU - Harada, Takeshi
AU  - Harada T
AD  - Department of Medicine and Bioregulatory Sciences, University of Tokushima 
      Graduate School of Medicine, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
FAU - Kurata, Keiji
AU  - Kurata K
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
FAU - Bae, Jooeun
AU  - Bae J
AD  - Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
FAU - Massefski, Walter
AU  - Massefski W
AD  - Department of Chemistry Instrumentation Facility, Massachusetts Institute of 
      Technology, Cambridge, MA, 02139, USA.
FAU - Anderson, Kenneth C
AU  - Anderson KC
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  - P01 CA155258/CA/NCI NIH HHS/United States
GR  - R01 CA050947/CA/NCI NIH HHS/United States
GR  - R01 CA178264/CA/NCI NIH HHS/United States
GR  - P50 CA100707/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 - 20200401
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CRBN protein, human)
RN  - 0 (Immunologic Factors)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase)
RN  - EC 2.7.10.2 (ZAP70 protein, human)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Cell Line, Tumor
MH  - Cells, Cultured
MH  - Cytotoxicity, Immunologic
MH  - Humans
MH  - Immunologic Factors/*pharmacology
MH  - Immunomodulation/drug effects
MH  - Killer Cells, Natural/*drug effects/immunology/*metabolism
MH  - Lymphocyte Activation/drug effects/immunology
MH  - Phosphorylation
MH  - Signal Transduction/*drug effects
MH  - T-Lymphocyte Subsets/immunology/metabolism/pathology
MH  - Ubiquitin-Protein Ligases/*metabolism
MH  - ZAP-70 Protein-Tyrosine Kinase/*metabolism
PMC - PMC7529681
MID - NIHMS1578112
COIS- Compliance with ethical standards Conflict of Interest KC Anderson serves on 
      advisory boards to Celgene, Millennium, Janssen, Sanofi, Bristol Myers Squibb, 
      Gilead, Precision Biosciences, and Tolero, and is a Scientific Founder of OncoPep 
      and C4 Therapeutics. The authors have no other relevant affiliations or financial 
      involvement with any organization or entity with a financial interest in or 
      financial conflict with the subject matter or materials discussed in the 
      manuscript apart from those disclosed.
EDAT- 2020/04/03 06:00
MHDA- 2021/01/14 06:00
PMCR- 2021/01/08
CRDT- 2020/04/03 06:00
PHST- 2019/11/05 00:00 [received]
PHST- 2020/03/18 00:00 [accepted]
PHST- 2020/03/17 00:00 [revised]
PHST- 2020/04/03 06:00 [pubmed]
PHST- 2021/01/14 06:00 [medline]
PHST- 2020/04/03 06:00 [entrez]
PHST- 2021/01/08 00:00 [pmc-release]
AID - 10.1038/s41375-020-0809-x [pii]
AID - 10.1038/s41375-020-0809-x [doi]
PST - ppublish
SO  - Leukemia. 2021 Jan;35(1):177-188. doi: 10.1038/s41375-020-0809-x. Epub 2020 Apr 
      1.