PMID- 31076446
OWN - NLM
STAT- In-Data-Review
LR  - 20190719
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 134
IP  - 3
DP  - 2019 Jul 18
TI  - Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, 
      and FLT3-ITD triple-mutated AML.
PG  - 263-276
LID - 10.1182/blood.2018862383 [doi]
AB  - FLT3, DNMT3A, and NPM1 are the most frequently mutated genes in cytogenetically
      normal acute myeloid leukemia (AML), but little is known about how these
      mutations synergize upon cooccurrence. Here we show that triple-mutated AML is
      characterized by high leukemia stem cell (LSC) frequency, an aberrant
      leukemia-specific GPR56 (high)CD34(low) immunophenotype, and synergistic
      upregulation of Hepatic Leukemia Factor (HLF). Cell sorting based on the LSC
      marker GPR56 allowed isolation of triple-mutated from DNMT3A/NPM1 double-mutated 
      subclones. Moreover, in DNMT3A R882-mutated patients, CpG hypomethylation at the 
      HLF transcription start site correlated with high HLF mRNA expression, which was 
      itself associated with poor survival. Loss of HLF via CRISPR/Cas9 significantly
      reduced the CD34(+)GPR56(+) LSC compartment of primary human triple-mutated AML
      cells in serial xenotransplantation assays. HLF knockout cells were more actively
      cycling when freshly harvested from mice, but rapidly exhausted when reintroduced
      in culture. RNA sequencing of primary human triple-mutated AML cells after
      shRNA-mediated HLF knockdown revealed the NOTCH target Hairy and Enhancer of
      Split 1 (HES1) and the cyclin-dependent kinase inhibitor CDKN1C/p57 as novel
      targets of HLF, potentially mediating these effects. Overall, our data establish 
      HLF as a novel LSC regulator in this genetically defined high-risk AML subgroup.
CI  - (c) 2019 by The American Society of Hematology.
FAU - Garg, Swati
AU  - Garg S
AUID- ORCID: http://orcid.org/0000-0002-3719-4342
AD  - Department of Medicine V, Hematology, Oncology and Rheumatology, University
      Hospital Heidelberg, Heidelberg, Germany.
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
FAU - Reyes-Palomares, Armando
AU  - Reyes-Palomares A
AUID- ORCID: http://orcid.org/0000-0002-0289-6889
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
AD  - Department of Biochemistry and Molecular Biology, Complutense University of
      Madrid, Madrid, Spain.
FAU - He, Lixiazi
AU  - He L
AD  - Department of Medicine V, Hematology, Oncology and Rheumatology, University
      Hospital Heidelberg, Heidelberg, Germany.
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
FAU - Bergeron, Anne
AU  - Bergeron A
AD  - Centre de Recherche du Centre Hospitalier Universitaire de Quebec, Centre de
      Recherche en Infectiologie du Centre Hospitalier de l'Universite Laval, Quebec
      City, QC, Canada.
FAU - Lavallee, Vincent-Philippe
AU  - Lavallee VP
AD  - Laboratory of Molecular Genetics of Stem Cells, Institute for Research in
      Immunology and Cancer, University of Montreal, Montreal, QC, Canada.
FAU - Lemieux, Sebastien
AU  - Lemieux S
AUID- ORCID: http://orcid.org/0000-0001-5477-1386
AD  - Department of Computer Science and Operations Research, University of Montreal,
      Montreal, QC, Canada.
FAU - Gendron, Patrick
AU  - Gendron P
AUID- ORCID: http://orcid.org/0000-0001-9829-2600
AD  - Department of Computer Science and Operations Research, University of Montreal,
      Montreal, QC, Canada.
FAU - Rohde, Christian
AU  - Rohde C
AD  - Department of Medicine V, Hematology, Oncology and Rheumatology, University
      Hospital Heidelberg, Heidelberg, Germany.
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
FAU - Xia, Jianglong
AU  - Xia J
AD  - Department of Medicine V, Hematology, Oncology and Rheumatology, University
      Hospital Heidelberg, Heidelberg, Germany.
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
FAU - Jagdhane, Prarabdha
AU  - Jagdhane P
AD  - Department of Medicine V, Hematology, Oncology and Rheumatology, University
      Hospital Heidelberg, Heidelberg, Germany.
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
FAU - Muller-Tidow, Carsten
AU  - Muller-Tidow C
AUID- ORCID: http://orcid.org/0000-0002-7166-5232
AD  - Department of Medicine V, Hematology, Oncology and Rheumatology, University
      Hospital Heidelberg, Heidelberg, Germany.
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
FAU - Lipka, Daniel B
AU  - Lipka DB
AUID- ORCID: http://orcid.org/0000-0001-5081-7869
AD  - Regulation of Cellular Differentiation Group, Division of Cancer Epigenomics,
      German Cancer Research Center, Heidelberg, Germany.
FAU - Imren, Suzan
AU  - Imren S
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Humphries, R Keith
AU  - Humphries RK
AD  - Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
FAU - Waskow, Claudia
AU  - Waskow C
AD  - Regeneration in Hematopoiesis, Leibniz-Institute on Aging-Fritz Lipmann
      Institute, Jena, Germany.
FAU - Vick, Binje
AU  - Vick B
AUID- ORCID: http://orcid.org/0000-0003-1956-2778
AD  - Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum Munchen,
      German Research Center for Environmental Health, Munich, Germany.
AD  - German Cancer Consortium, partner site Munich, Germany.
FAU - Jeremias, Irmela
AU  - Jeremias I
AUID- ORCID: http://orcid.org/0000-0003-1773-7677
AD  - Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum Munchen,
      German Research Center for Environmental Health, Munich, Germany.
AD  - German Cancer Consortium, partner site Munich, Germany.
FAU - Richard-Carpentier, Guillaume
AU  - Richard-Carpentier G
AUID- ORCID: http://orcid.org/0000-0001-6452-8814
AD  - The Quebec Leukemia Cell Bank, Research Centre, Maisonneuve-Rosemont Hospital,
      Montreal, QC, Canada.
FAU - Hebert, Josee
AU  - Hebert J
AD  - The Quebec Leukemia Cell Bank, Research Centre, Maisonneuve-Rosemont Hospital,
      Montreal, QC, Canada.
AD  - Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal,
      QC, Canada.
AD  - Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC,
      Canada; and.
FAU - Sauvageau, Guy
AU  - Sauvageau G
AD  - Laboratory of Molecular Genetics of Stem Cells, Institute for Research in
      Immunology and Cancer, University of Montreal, Montreal, QC, Canada.
AD  - Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal,
      QC, Canada.
AD  - Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC,
      Canada; and.
FAU - Zaugg, Judith B
AU  - Zaugg JB
AUID- ORCID: http://orcid.org/0000-0001-8324-4040
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
FAU - Barabe, Frederic
AU  - Barabe F
AD  - Centre de Recherche du Centre Hospitalier Universitaire de Quebec, Centre de
      Recherche en Infectiologie du Centre Hospitalier de l'Universite Laval, Quebec
      City, QC, Canada.
AD  - Department of Medicine, Universite Laval, Quebec City, QC, Canada.
FAU - Pabst, Caroline
AU  - Pabst C
AUID- ORCID: http://orcid.org/0000-0001-9716-5909
AD  - Department of Medicine V, Hematology, Oncology and Rheumatology, University
      Hospital Heidelberg, Heidelberg, Germany.
AD  - Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg,
      Germany.
AD  - European Molecular Biology Laboratory, Heidelberg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20190510
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
SB  - AIM
SB  - IM
EDAT- 2019/05/12 06:00
MHDA- 2019/05/12 06:00
CRDT- 2019/05/12 06:00
PHST- 2018/07/10 00:00 [received]
PHST- 2019/05/02 00:00 [accepted]
PHST- 2019/05/12 06:00 [pubmed]
PHST- 2019/05/12 06:00 [medline]
PHST- 2019/05/12 06:00 [entrez]
AID - blood.2018862383 [pii]
AID - 10.1182/blood.2018862383 [doi]
PST - ppublish
SO  - Blood. 2019 Jul 18;134(3):263-276. doi: 10.1182/blood.2018862383. Epub 2019 May
      10.