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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

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 5

STC1 induces reduction of HSPC proliferation in AML in vivo.

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STC1 induces reduction of HSPC proliferation in AML in vivo.
(A–C) MSC s...
(A–C) MSC scaffolds with normal CD34+ cells were implanted into NSG-S mice. rSTC1 was injected every other day for 10 days starting on day 2 after implantation. Three mice/group with 4 scaffolds per mouse. (B) CTV+ cells among total human CD45+ and CD34+ cells. (C) LTC-IC frequency of sorted human CD45+lineage– cells. (D–F) MSC scaffolds with normal CD34+ cells and AML cell lines (U937, OCI-AML3) were implanted into NSG-S mice. IgG or anti-STC1 antibody was injected subcutaneously every other day for 2 weeks. Seven mice/group with 2–4 scaffolds per mouse. (E) Absolute cell counts of AML and normal human CD45+ cells per mouse. (F) CTVbright cells among CD34+ cells and normalized to CD34+ cells alone. Each dot represents data from 2–6 pooled scaffolds implanted in 1 recipient. *P < 0.05 by 2-tailed paired Student’s t test (B, C, and F) or Wilcoxon’s matched-pairs signed-rank test (E).

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