[HTML][HTML] Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML

CHM Jamieson, LE Ailles, SJ Dylla… - … England Journal of …, 2004 - Mass Medical Soc
CHM Jamieson, LE Ailles, SJ Dylla, M Muijtjens, C Jones, JL Zehnder, J Gotlib, K Li…
New England Journal of Medicine, 2004Mass Medical Soc
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 β-catenin–signaling pathway. We investigated
whether leukemic stem cells in CML also use the β-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 …
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 β-catenin–signaling pathway. We investigated whether leukemic stem cells in CML also use the β-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, β-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 β-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 β-catenin activation was tested by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor of the β-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 β-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 β-catenin in CML granulocyte–macrophage progenitors appears to enhance the self-renewal activity and leukemic potential of these cells.
The New England Journal Of Medicine