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Title: Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation
Authors: Mead, A.J
Neo, W.H
Barkas, N
Matsuoka, S
Giustacchini, A
Facchini, R
Thongjuea, S
Jamieson, L
Booth, C.A.G
Fordham, N
Di Genua, C
Atkinson, D
Chowdhury, O
Repapi, E
Gray, N
Kharazi, S
Clark, S.-A
Bouriez, T
Woll, P
Suda, T 
Nerlov, C
Jacobsen, S.E.W
Keywords: CD135 antigen
messenger RNA
tumor necrosis factor
CD135 antigen
FLT3 protein, human
nonsteroid antiinflammatory agent
tumor necrosis factor
animal cell
bone marrow stroma cell
endothelium cell
gene expression
hematopoietic stem cell
internal tandem duplication
mesenchymal stroma cell
myeloproliferative disorder
priority journal
protein expression
single cell analysis
stem cell niche
tandem repeat
antagonists and inhibitors
bone marrow cell
bone marrow transplantation
C57BL mouse
cell culture
cell proliferation
drug effects
gene expression profiling
hematopoietic stem cell
reverse transcription polymerase chain reaction
stem cell niche
tandem repeat
transgenic mouse
Anti-Inflammatory Agents, Non-Steroidal
Bone Marrow Cells
Bone Marrow Transplantation
Cell Proliferation
Cells, Cultured
fms-Like Tyrosine Kinase 3
Gene Expression Profiling
Hematopoietic Stem Cells
Mesenchymal Stromal Cells
Mice, Inbred C57BL
Mice, Transgenic
Reverse Transcriptase Polymerase Chain Reaction
Single-Cell Analysis
Stem Cell Niche
Tandem Repeat Sequences
Tumor Necrosis Factor-alpha
Issue Date: 2017
Publisher: Rockefeller University Press
Citation: Mead, A.J, Neo, W.H, Barkas, N, Matsuoka, S, Giustacchini, A, Facchini, R, Thongjuea, S, Jamieson, L, Booth, C.A.G, Fordham, N, Di Genua, C, Atkinson, D, Chowdhury, O, Repapi, E, Gray, N, Kharazi, S, Clark, S.-A, Bouriez, T, Woll, P, Suda, T, Nerlov, C, Jacobsen, S.E.W (2017). Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation. Journal of Experimental Medicine 214 (7) : 2005-2021. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell-extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD-driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology. © 2017 Mead et al.
Source Title: Journal of Experimental Medicine
ISSN: 00221007
DOI: 10.1084/jem.20161418
Rights: Attribution 4.0 International
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