PMID- 15306667
OWN - NLM
STAT- MEDLINE
DCOM- 20040818
LR  - 20220408
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Linking)
VI  - 351
IP  - 7
DP  - 2004 Aug 12
TI  - Granulocyte-macrophage progenitors as candidate leukemic stem cells in 
      blast-crisis CML.
PG  - 657-67
AB  - BACKGROUND: The progression of chronic myelogenous leukemia (CML) to blast crisis 
      is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic 
      stem cells, the process of self-renewal involves the beta-catenin-signaling 
      pathway. We investigated whether leukemic stem cells in CML also use the 
      beta-catenin pathway for self-renewal. METHODS: We used fluorescence-activated 
      cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, 
      granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors from 
      marrow during several phases of CML and from normal marrow. BCR-ABL, 
      beta-catenin, and LEF-1 transcripts were compared by means of a quantitative 
      reverse-transcriptase-polymerase-chain-reaction assay in normal and CML 
      hematopoietic stem cells and granulocyte-macrophage progenitors. Confocal 
      fluorescence microscopy and a lymphoid enhancer factor/T-cell factor reporter 
      assay were used to detect nuclear beta-catenin in these cells. In vitro replating 
      assays were used to identify self-renewing cells as candidate leukemic stem 
      cells, and the dependence of self-renewal on beta-catenin activation was tested 
      by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor 
      of the beta-catenin pathway. RESULTS: The granulocyte-macrophage progenitor pool 
      from patients with CML in blast crisis and imatinib-resistant CML was expanded, 
      expressed BCR-ABL, and had elevated levels of nuclear beta-catenin as compared 
      with the levels in progenitors from normal marrow. Unlike normal 
      granulocyte-macrophage progenitors, CML granulocyte-macrophage progenitors formed 
      self-renewing, replatable myeloid colonies, and in vitro self-renewal capacity 
      was reduced by enforced expression of axin. CONCLUSIONS: Activation of 
      beta-catenin in CML granulocyte-macrophage progenitors appears to enhance the 
      self-renewal activity and leukemic potential of these cells.
CI  - Copyright 2004 Massachusetts Medical Society
FAU - Jamieson, Catriona H M
AU  - Jamieson CH
AD  - Division of Hematology, Stanford University School of Medicine, Stanford, Calif 
      94305-5323, USA.
FAU - Ailles, Laurie E
AU  - Ailles LE
FAU - Dylla, Scott J
AU  - Dylla SJ
FAU - Muijtjens, Manja
AU  - Muijtjens M
FAU - Jones, Carol
AU  - Jones C
FAU - Zehnder, James L
AU  - Zehnder JL
FAU - Gotlib, Jason
AU  - Gotlib J
FAU - Li, Kevin
AU  - Li K
FAU - Manz, Markus G
AU  - Manz MG
FAU - Keating, Armand
AU  - Keating A
FAU - Sawyers, Charles L
AU  - Sawyers CL
FAU - Weissman, Irving L
AU  - Weissman IL
LA  - eng
GR  - 2PO1CA49605/CA/NCI NIH HHS/United States
GR  - 5T32AI07290/AI/NIAID NIH HHS/United States
GR  - CA55209/CA/NCI NIH HHS/United States
GR  - CA86017/CA/NCI NIH HHS/United States
GR  - K23 HL04409/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (CTNNB1 protein, human)
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (LEF1 protein, human)
RN  - 0 (Lymphoid Enhancer-Binding Factor 1)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (beta Catenin)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
SB  - IM
CIN - N Engl J Med. 2004 Aug 12;351(7):634-6. PMID: 15306664
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/therapeutic use
MH  - Benzamides
MH  - Blast Crisis/*physiopathology
MH  - Colony-Forming Units Assay
MH  - Cytoskeletal Proteins/*metabolism
MH  - DNA-Binding Proteins/metabolism
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Fusion Proteins, bcr-abl/metabolism
MH  - Granulocytes/cytology
MH  - Hematopoietic Stem Cells/metabolism/*physiology
MH  - Humans
MH  - Imatinib Mesylate
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug 
      therapy/metabolism/*physiopathology
MH  - Lymphoid Enhancer-Binding Factor 1
MH  - Macrophages/cytology
MH  - Male
MH  - Microscopy, Confocal
MH  - Middle Aged
MH  - Piperazines/therapeutic use
MH  - Pyrimidines/therapeutic use
MH  - RNA, Neoplasm
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Trans-Activators/*metabolism
MH  - Transcription Factors/metabolism
MH  - beta Catenin
EDAT- 2004/08/13 05:00
MHDA- 2004/08/19 05:00
CRDT- 2004/08/13 05:00
PHST- 2004/08/13 05:00 [pubmed]
PHST- 2004/08/19 05:00 [medline]
PHST- 2004/08/13 05:00 [entrez]
AID - 351/7/657 [pii]
AID - 10.1056/NEJMoa040258 [doi]
PST - ppublish
SO  - N Engl J Med. 2004 Aug 12;351(7):657-67. doi: 10.1056/NEJMoa040258.