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Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia
Alexander Waclawiczek, … , David Taussig, Dominique Bonnet
Alexander Waclawiczek, … , David Taussig, Dominique Bonnet
Published May 4, 2020
Citation Information: J Clin Invest. 2020;130(6):3038-3050. https://doi.org/10.1172/JCI133187.
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Research Article Hematology Article has an altmetric score of 6

Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia

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Abstract

Acute myeloid leukemia (AML) disrupts the generation of normal blood cells, predisposing patients to hemorrhage, anemia, and infections. Differentiation and proliferation of residual normal hematopoietic stem and progenitor cells (HSPCs) are impeded in AML-infiltrated bone marrow (BM). The underlying mechanisms and interactions of residual hematopoietic stem cells (HSCs) within the leukemic niche are poorly understood, especially in the human context. To mimic AML infiltration and dissect the cellular crosstalk in human BM, we established humanized ex vivo and in vivo niche models comprising AML cells, normal HSPCs, and mesenchymal stromal cells (MSCs). Both models replicated the suppression of phenotypically defined HSPC differentiation without affecting their viability. As occurs in AML patients, the majority of HSPCs were quiescent and showed enrichment of functional HSCs. HSPC suppression was largely dependent on secreted factors produced by transcriptionally remodeled MSCs. Secretome analysis and functional validation revealed MSC-derived stanniocalcin 1 (STC1) and its transcriptional regulator HIF-1α as limiting factors for HSPC proliferation. Abrogation of either STC1 or HIF-1α alleviated HSPC suppression by AML. This study provides a humanized model to study the crosstalk among HSPCs, leukemia, and their MSC niche, and a molecular mechanism whereby AML impairs normal hematopoiesis by remodeling the mesenchymal niche.

Authors

Alexander Waclawiczek, Ashley Hamilton, Kevin Rouault-Pierre, Ander Abarrategi, Manuel Garcia Albornoz, Farideh Miraki-Moud, Nourdine Bah, John Gribben, Jude Fitzgibbon, David Taussig, Dominique Bonnet

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Figure 7

HIF-1α knockdown in MSCs partially rescues HSPC proliferation in AML.

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HIF-1α knockdown in MSCs partially rescues HSPC proliferation in AML.
(A...
(A–C) MSCs were lentivirally transduced to express the shCTL or shHIF-1α construct and cocultured with CD34+ cells alone or AML cell lines with PBS or rSTC1. CD34+ cells alone were used as control and reference for normalization. Data are presented as box-and-whisker plots, with bounds from 25th to 75th percentile, median line, and whiskers ranging from smallest to largest values of 3 measurements per AML cell line (KG1A, OCI-AML3, U937, ML1, MOLM-13). (B) CTVbright cells among CD34+ cells. (C) Proportions of normal HSPCs among normal CD45+ cells. (D–F) MSCs were lentivirally transduced to express shRNA against RFP (shCTL) or shHIF-1α construct, and seeded in scaffolds before the injection of normal CD34+ cells alone or with the AML cell line U937. Each dot represents data from 1 scaffold. Five mice/group with 2–4 scaffolds per mouse. (E) Cell counts of total normal CD45+ cells. (F) Proportions of lineage–CD34+ cells among normal CD45+ cells. (G) Proportions of EdU+ cells among normal CD45+ cells. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by Friedman’s test with Dunn’s test (B and C) or Mann-Whitney U test (E–G).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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