Differential niche and Wnt requirements during acute myeloid leukemia progression

Lane, Steven W., Wang, Yingzi J., Lo Celso, Cristina, Ragu, Christine, Bullinger, Lars, Sykes, Stephen M., Ferraro, Francesca, Shterental, Sebastian, Lin, Charles P., Gilliland, D. Gary, Scadden, David T., Armstrong, Scott A. and Williams, David A. (2011) Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood, 118 10: 2849-2856. doi:10.1182/blood-2011-03-345165

Author Lane, Steven W.
Wang, Yingzi J.
Lo Celso, Cristina
Ragu, Christine
Bullinger, Lars
Sykes, Stephen M.
Ferraro, Francesca
Shterental, Sebastian
Lin, Charles P.
Gilliland, D. Gary
Scadden, David T.
Armstrong, Scott A.
Williams, David A.
Title Differential niche and Wnt requirements during acute myeloid leukemia progression
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
Publication date 2011-09
Sub-type Article (original research)
DOI 10.1182/blood-2011-03-345165
Volume 118
Issue 10
Start page 2849
End page 2856
Total pages 8
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Abstract Hematopoietic stem cells (HSCs) engage in complex bidirectional signals with the hematopoietic microenvironment (HM), and there is emerging evidence that leukemia stem cells (LSCs) may use similar interactions. Using a syngeneic retroviral model of MLL-AF9 induced acute myeloid leukemia (AML), we have identified 2 different stages of leukemia progression, propagated by "pre-LSCs" and established leukemia (LSCs) and compared the homing properties of these distinctive entities to that of normal HSCs. The homing and microlocalization of pre-LSCs was most similar to long-term HSCs and was dependent on cell-intrinsic Wnt signaling. In contrast, the homing of established LSCs was most similar to that of committed myeloid progenitors and distinct from HSCs. Although osteoblast-derived Dickkopf-1, a potent Wnt inhibitor known to impair HSC function, dramatically impaired normal HSC localization within the bone marrow, it did not affect pre-LSCs, LSC homing, or AML development. Mechanistically, cell-intrinsic Wnt activation was observed in human and murineAMLsamples, explaining the independence of MLL-AF9 LSCs from nichederived Wnt signals. These data identify differential engagement of HM associated with leukemic progression and identify an LSC niche that is physically distinct and independent of the constraints of Wnt signaling that apply to normal HSCs.
Keyword Stem-Cell Niche
Hematopoietic Stem
Progenitor Cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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