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

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 6

HIF-1α stabilization in MSCs induces STC1 secretion in AML.

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HIF-1α stabilization in MSCs induces STC1 secretion in AML. (A) Common g...
(A) Common gene ontology of upregulated genes from MSCs cocultured with AML cell lines or patient samples. logFE, logarithmic fold expression. (B) mRNA expression of hypoxia-regulated genes in MSCs. Data were obtained from 2–9 measurements of MSCs cultured alone at 20% O2 (normoxia) (n = 9) or 3% O2 (hypoxia) (n = 2), or cocultured with CB CD34+ cells (n = 4) or AML cell lines (n = 3)/patient samples (n = 4) for 5 days at 20% O2; measured by qPCR and normalized to MSCs (normoxia). AML patient samples: AML6–9. Measurements from AML cell lines, n = 3–4. (C) Immunoblot of HIF-1α and β-actin (loading control) of whole cell lysate of MSCs cultured alone or with AML patient samples. AML1, -3, and -7. (D–F) MSCs were lentivirally transduced to express shRNA against dsRed fluorescent protein (RFP; shCTL) or an shHIF-1α construct. (D) mRNA expression of hypoxia-regulated genes in cocultured MSCs normalized to shCTL-MSCs + CD34+ cells alone. AML7. n =2. (E) STC1 secretion in supernatant of MSCs + CD34+ cells alone or +AML5, -7, and -8. n = 3. (F) STC1 mRNA expression in transduced MSCs sorted from pooled scaffolds with CB CD34+ alone or +AML cell line U937. Four mice/group with 2 scaffolds per mouse. Data are presented as mean ± SEM, except in D, which shows mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 by Kruskal-Wallis test with Dunn’s test (A), 2-tailed Student t test corrected with the Holm-Šidák method (D and E), and ANOVA with Tukey’s test (F).