Leukemia stem cells occupy niches that are physically distinct and independent of the normal constraints that apply to hematopoietic stem cells

Lane, S. W., Sykes, S. M., Ferraro, F., Lin, C. P., Gilliland, D. G., Williams, D. A., Scadden, D. T. and Lo Celso, C. (2010). Leukemia stem cells occupy niches that are physically distinct and independent of the normal constraints that apply to hematopoietic stem cells. In: 39th Annual Scientific Meeting of the ISEH Society for Hematology and Stem Cells, Melbourne Australia, (S38-S38). 15-18 September 2010. doi:10.1016/j.exphem.2010.07.008


Author Lane, S. W.
Sykes, S. M.
Ferraro, F.
Lin, C. P.
Gilliland, D. G.
Williams, D. A.
Scadden, D. T.
Lo Celso, C.
Title of paper Leukemia stem cells occupy niches that are physically distinct and independent of the normal constraints that apply to hematopoietic stem cells
Conference name 39th Annual Scientific Meeting of the ISEH Society for Hematology and Stem Cells
Conference location Melbourne Australia
Conference dates 15-18 September 2010
Journal name Experimental Hematology   Check publisher's open access policy
Place of Publication Philadelphia, PA, United States
Publisher Elsevier
Publication Year 2010
Sub-type Published abstract
DOI 10.1016/j.exphem.2010.07.008
ISSN 0301-472X
1873-2399
Volume 38
Issue 9 (Suppl.)
Start page S38
End page S38
Total pages 1
Language eng
Formatted Abstract/Summary
Hematopoietic stem cells (HSC) require complex bidirectional signals from the hematopoietic microenvironment (HM) and there is emerging evidence that leukemia stem cells (LSC) reside in similar niches within the HM. Existing models of LSC-niche interactions have used xenograft transplantation experiments raising concerns about immunological or cross-species incompatibility. Moreover, the precise components that constrain LSC within the HM have not been fully characterized. We utilized a  syngeneic retroviral model of MLL-AF9 induced acute myeloid leukemia (AML) to evaluate LSC-HM interactions and characterize the requirement of key self-renewal pathways in LSC-HM crosstalk. AML was generated using retroviral transduction of murine bone marrow or granulocyte macrophage progenitors (GMP) with the MLL-AF9 fusion oncogene. MLL-AF9 transformed TOPGal (Wnt reporter) bone marrow showed activated canonical Wnt signaling. LSC, (immunophenotype as  lineagelowcKithighSca1-FcGRII/III+CD34+), were FACS purified and transplanted into lethally irradiated syngeneic mice expressing GFP in osteoblasts  (2.3kbColl1alpha-GFP). The homing and microlocalization of LSC was examined using live, 3 dimensional two-photon confocal hybrid imaging of the calvarium. LSC localized near osteoblasts similar to GMP but farther than HSC (median distance 23.7µm LSC, 22.1µm GMP, 10.6µm HSC, p=ns LSC vs. GMP, p<0.01 LSC vs. HSC). We utilized transgenic mice that expressed Dkk1, a potent Wnt pathway inhibitor, from osteoblasts to evaluate the effects of Wnt inhibition on HSC and LSC homing. HSC localized farther from osteoblasts in Dkk1 mice (median 11µm WT vs. 50µm Dkk1), correlating with a defect in hematopoietic reconstitution. In contrast, LSC homing was not impaired in Dkk1 mice. AML developed in Dkk1 mice with similar latency of disease and immunophenotype to WT hosts. There was no inhibition of Wnt signaling (TOPGal reporter) in LSC derived from Dkk1 mice. Our data identify a LSC niche that is both physically distinct and independent of the normal constraints of Wnt signaling that apply to HSC.
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Conference Paper
Collection: School of Medicine Publications
 
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