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 3

MSC-secreted STC1 is upregulated in AML patient plasma.

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MSC-secreted STC1 is upregulated in AML patient plasma. (A) mRNA express...
(A) mRNA expression of STC1 in MSCs cultured alone (n = 4), +CB CD34+ cells (n = 4), or +AML cell lines (n = 3)/patient samples (n = 3) for 5 days; measured by quantitative PCR (qPCR) and normalized to MSCs cultured alone (n = 4). AML patient samples: AML6, -8, and -9. (B) STC1 protein in supernatant of MSCs cocultured with CD34+ cells, +AML cell lines (n = 7)/patient samples (n = 8); measured by ELISA and normalized to MSCs + CD34+ cells (CD34+ alone). AML1–5, -8, -10, and -11. STC1 protein was measured by ELISA (C) in AML patient BM plasma from nonmatched diagnosis (n = 27) and remission (n = 21) samples and normalized to remission and (D) from 5 matched diagnosis/remission samples. (E) STC1 protein in AML patient PB plasma at diagnosis (n = 26) and healthy donors (n = 20). (F) Correlation of STC1 protein concentration between BM and PB plasma (n = 13). (G) Correlation of platelet (PLT) count in PB and STC1 protein in PB plasma from AML patients at diagnosis (n = 26). Data are presented as mean ± SEM, with each patient sample as a dot (C–G) or unique symbol (A and B). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by Kruskal-Wallis test with Dunn’s test (A and B), Mann-Whitney U test (C and E), Wilcoxon’s matched-pairs signed-rank test (D), and Pearson’s correlation and linear regression test (F and G).