PMID- 24166297
OWN - NLM
STAT- MEDLINE
DCOM- 20140710
LR  - 20240321
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 28
IP  - 5
DP  - 2014 May
TI  - Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL 
      leukemia stem cells.
PG  - 1081-91
LID - 10.1038/leu.2013.316 [doi]
AB  - Through a targeted knockdown (KD) screen of chromatin regulatory genes, we 
      identified the EP400 complex components EPC1 and EPC2 as critical oncogenic 
      cofactors in acute myeloid leukemia (AML). EPC1 and EPC2 were required for the 
      clonogenic potential of human AML cells of multiple molecular subtypes. Focusing 
      on MLL-mutated AML as an exemplar, Epc1 or Epc2 KD-induced apoptosis of murine 
      MLL-AF9 AML cells and abolished leukemia stem cell potential. By contrast, normal 
      hematopoietic stem and progenitor cells (HSPC) were spared. Similar selectivity 
      was observed for human primary AML cells versus normal CD34(+) HSPC. In keeping 
      with these distinct functional consequences, Epc1 or Epc2 KD-induced divergent 
      transcriptional consequences in murine MLL-AF9 granulocyte-macrophage 
      progenitor-like (GMP) cells versus normal GMP, with a signature of increased MYC 
      activity in leukemic but not normal cells. This was caused by accumulation of MYC 
      protein and was also observed following KD of other EP400 complex genes. 
      Pharmacological inhibition of MYC:MAX dimerization, or concomitant MYC KD, 
      reduced apoptosis following EPC1 KD, linking the accumulation of MYC to cell 
      death. Therefore, EPC1 and EPC2 are components of a complex that directly or 
      indirectly serves to prevent MYC accumulation and AML cell apoptosis, thus 
      sustaining oncogenic potential.
FAU - Huang, X
AU  - Huang X
AD  - Leukemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, UK.
FAU - Spencer, G J
AU  - Spencer GJ
AD  - Leukemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, UK.
FAU - Lynch, J T
AU  - Lynch JT
AD  - Leukemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, UK.
FAU - Ciceri, F
AU  - Ciceri F
AD  - Leukemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, UK.
FAU - Somerville, T D D
AU  - Somerville TD
AD  - Leukemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, UK.
FAU - Somervaille, T C P
AU  - Somervaille TC
AD  - Leukemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, UK.
LA  - eng
GR  - 19280/CRUK_/Cancer Research UK/United Kingdom
GR  - A10300/CRUK_/Cancer Research UK/United Kingdom
GR  - C5759/A12328/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131029
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Chromosomal Proteins, Non-Histone)
RN  - 0 (EPC1 protein, human)
RN  - 0 (KMT2A protein, human)
RN  - 0 (Repressor Proteins)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Chromosomal Proteins, Non-Histone/genetics/*physiology
MH  - Flow Cytometry
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - Leukemia/genetics/metabolism/*pathology
MH  - Mice
MH  - Myeloid-Lymphoid Leukemia Protein/*genetics
MH  - Neoplastic Stem Cells/*pathology
MH  - *Oncogenes
MH  - Polymerase Chain Reaction
MH  - Repressor Proteins/genetics/*physiology
PMC - PMC3998875
MID - EMS56062
OID - NLM: EMS56062
EDAT- 2013/10/30 06:00
MHDA- 2014/07/11 06:00
PMCR- 2014/11/01
CRDT- 2013/10/30 06:00
PHST- 2013/05/28 00:00 [received]
PHST- 2013/09/30 00:00 [revised]
PHST- 2013/10/22 00:00 [accepted]
PHST- 2013/10/30 06:00 [entrez]
PHST- 2013/10/30 06:00 [pubmed]
PHST- 2014/07/11 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - leu2013316 [pii]
AID - 10.1038/leu.2013.316 [doi]
PST - ppublish
SO  - Leukemia. 2014 May;28(5):1081-91. doi: 10.1038/leu.2013.316. Epub 2013 Oct 29.