Niche-mediated Depletion of the Normal Hematopoietic Stem Cell Reservoir by Flt3-ITD-induced Myeloproliferation

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2017 Jun 23

PMID 28637883

Citations 31

Authors

Adam J Mead

Wen Hao Neo

Nikolaos Barkas

Sahoko Matsuoka

Alice Giustacchini

Raffaella Facchini

Supat Thongjuea

Lauren Jamieson

Christopher A G Booth

Nicholas Fordham

Cristina Di Genua

Deborah Atkinson

Onima Chowdhury

Emmanouela Repapi

Nicki Gray

Shabnam Kharazi

Sally-Ann Clark

Tiphaine Bouriez

Petter Woll

Toshio Suda

Claus Nerlov

Sten Eirik W Jacobsen

Affiliations

Soon will be listed here.

Abstract

Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), internal tandem duplications ( ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between 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.

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