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 2

AML induces HSPC quiescence via mesenchymal niche–secreted factors.

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AML induces HSPC quiescence via mesenchymal niche–secreted factors. (A–C...
(A–C) CD34+ cells were cultured alone or with AML cell lines with 100 ng/mL SCF/FLT-3L and 20 ng/mL TPO + 10% FBS with (+) and without (–) MSCs. CD34+ cells alone were used as control and reference for normalization. Cell counts of CD34+ cells after 4 days (B) and CTVbright cells among CD34+ cells (C). (D and E) MSCs were cultured alone (n = 6) or cocultured with AML cell lines expressing iCASP9 (n = 5) for 5 days. AP1903 (5 nM) was added on day 4, inducing apoptosis and allowing the removal of AML. CB CD34+ cells were then added in fresh medium to the preconditioned MSCs for 48 hours. (E) Percentage of CTVbright cells retrieved after 48 hours. (F) CD34+ cells cocultured with MSCs and AML cell lines (n = 3) directly or separated from MSCs and AML via a 0.4-μm Transwell insert. (G) CTVbright cells among CD34+ cells. (H) Gene expression analysis of MS-5 cells after coculture for 7 days with AML cell lines (n = 7), AML patient samples (n = 2), or normal CD34+ cells (n = 3) as control. Heatmap of shared upregulated secreted factors with logarithmic fold change (logFC) > 1. FC, fold change. Data are presented as mean ± SEM, with each AML cell line or patient sample as a unique symbol (E) or as box-and-whisker plots, with bounds from 25th to 75th percentile, median line, and whiskers ranging from smallest to largest values of 4 measurements from CD34+ alone or +AML cell lines (n = 3–4) (B, C, and G). *P < 0.05,**P < 0.01, ***P < 0.001, ****P < 0.0001 by Kruskal-Wallis test with Dunn’s test (B, C, and G) and Mann-Whitney U test (E).