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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 4

STC1 induces reduction of CB and BM HSPC proliferation ex vivo.

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STC1 induces reduction of CB and BM HSPC proliferation ex vivo.
(A and B...
(A and B) MSCs were cocultured with CB CD34+ cells and supplemented with rSTC1 or PBS (vehicle control) for 5 days. (B) Quantification of cell count. (C–F) Results of GSEA of HSPCs (CD34+CD38–) cocultured for 48 hours with MSCs and supplemented with rSTC1 or PBS (vehicle control) (n = 3). (G) Proportions of Ki-67– quiescent cells in CB CD34+ cells treated with rSTC1 and PBS. (H) LTC-IC frequency in sorted CD34+ cells. (I–L) MSCs were cocultured with BM CD34+ from 2 donors and supplemented with rSTC1 or PBS (vehicle control) for 5 days. (I) Total expansion of hCD45+ cells relative to day 0. Quantification of (J) HPCs and HSPCs normalized to PBS on day 5 and (K) proportions of HPCs/HSPCs that had undergone 0–1 divisions normalized to PBS. (L) LTC-IC frequency per CD34+ cells. Data are presented as mean ± SEM, n = 4–7. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test. NES, normalized enrichment score.

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

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