PMID- 29925903
OWN - NLM
STAT- MEDLINE
DCOM- 20190530
LR  - 20200225
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 33
IP  - 1
DP  - 2019 Jan
TI  - Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative 
      disease in mice.
PG  - 110-121
LID - 10.1038/s41375-018-0166-1 [doi]
AB  - Growth factor independent 1 (Gfi1) controls myeloid differentiation by regulating 
      gene expression and limits the activation of p53 by facilitating its 
      de-methylation at Lysine 372. In human myeloid leukemia, low GFI1 levels 
      correlate with an inferior prognosis. Here, we show that knockdown (KD) of Gfi1 
      in mice causes a fatal myeloproliferative disease (MPN) that could progress to 
      leukemia after additional mutations. Both KO and KD mice accumulate myeloid cells 
      that show signs of metabolic stress and high levels of reactive oxygen species. 
      However, only KO cells have elevated levels of Lysine 372 methylated p53. This 
      suggests that in contrast to absence of GFI1, KD of GFI1 leads to the 
      accumulation of myeloid cells because sufficient amount of GFI1 is present to 
      impede p53-mediated cell death, leading to a fatal MPN. The combination of 
      myeloid accumulation and the ability to counteract p53 activity under metabolic 
      stress could explain the role of reduced GF1 expression in human myeloid 
      leukemia.
FAU - Fraszczak, Jennifer
AU  - Fraszczak J
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
AD  - Departement de microbiologie, infectiologie et immunologie, Universite de 
      Montreal, Montreal, QC, Canada.
FAU - Vadnais, Charles
AU  - Vadnais C
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
AD  - Departement de microbiologie, infectiologie et immunologie, Universite de 
      Montreal, Montreal, QC, Canada.
FAU - Rashkovan, Marissa
AU  - Rashkovan M
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
AD  - Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
FAU - Ross, Julie
AU  - Ross J
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
AD  - Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
FAU - Beauchemin, Hugues
AU  - Beauchemin H
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
FAU - Chen, Riyan
AU  - Chen R
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
FAU - Grapton, Damien
AU  - Grapton D
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
AD  - Departement de microbiologie, infectiologie et immunologie, Universite de 
      Montreal, Montreal, QC, Canada.
FAU - Khandanpour, Cyrus
AU  - Khandanpour C
AUID- ORCID: 0000-0003-4655-6269
AD  - Department of Hematology, University Hospital, Essen, Germany.
AD  - Department of Medicine A, Hematology, Oncology and Pneumology, University 
      Hospital Munster, Munster, Germany.
FAU - Moroy, Tarik
AU  - Moroy T
AD  - Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada. 
      Tarik.Moroy@ircm.qc.ca.
AD  - Departement de microbiologie, infectiologie et immunologie, Universite de 
      Montreal, Montreal, QC, Canada. Tarik.Moroy@ircm.qc.ca.
AD  - Division of Experimental Medicine, McGill University, Montreal, QC, Canada. 
      Tarik.Moroy@ircm.qc.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180620
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Gfi1 protein, mouse)
RN  - 0 (TRPC Cation Channels)
RN  - 0 (Transcription Factors)
RN  - 0 (transient receptor potential cation channel, subfamily C, member 1)
SB  - IM
MH  - Animals
MH  - *Cell Differentiation
MH  - DNA-Binding Proteins/*physiology
MH  - Leukemia, Myeloid/etiology/metabolism/*pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Cells/metabolism/*pathology
MH  - Myeloproliferative Disorders/etiology/metabolism/*pathology
MH  - Oxidative Stress
MH  - TRPC Cation Channels/physiology
MH  - Transcription Factors/*physiology
PMC - PMC6326955
COIS- The authors declare that they have no conflict of interest.
EDAT- 2018/06/22 06:00
MHDA- 2019/05/31 06:00
PMCR- 2018/06/20
CRDT- 2018/06/22 06:00
PHST- 2018/02/05 00:00 [received]
PHST- 2018/05/10 00:00 [accepted]
PHST- 2018/04/25 00:00 [revised]
PHST- 2018/06/22 06:00 [pubmed]
PHST- 2019/05/31 06:00 [medline]
PHST- 2018/06/22 06:00 [entrez]
PHST- 2018/06/20 00:00 [pmc-release]
AID - 10.1038/s41375-018-0166-1 [pii]
AID - 166 [pii]
AID - 10.1038/s41375-018-0166-1 [doi]
PST - ppublish
SO  - Leukemia. 2019 Jan;33(1):110-121. doi: 10.1038/s41375-018-0166-1. Epub 2018 Jun 
      20.