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

Alexander Waclawiczek,Kevin Rouault-Pierre,Ander Abarrategi,David Taussig,Jude Fitzgibbon,Nourdine Bah,Manuel Garcia Albornoz,Dominique Bonnet,Ashley Hamilton,Farideh Miraki-Moud,John Gribben

doi:10.1172/jci133187

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.

Highlights

The hematopoietic system is a conglomerate of multiple lineages with the hematopoietic stem cell (HSC) as common origin [1]
Consistent with this, when we compared the expansion of cord blood (CB) CD34+ cells cultured with healthy donor mesenchymal stromal cells (MSCs) alone (CD34+-alone) or together with Acute myeloid leukemia (AML) cell lines (+AML cell lines) for 4 days (Figure 1A), we observed that AML cell lines decreased the retrieval of normal hematopoietic cells by 38% ± 19.5% (Figure 1B)
The viability of normal hematopoietic stem and progenitor cells (HSPCs) did not differ between control and AML conditions and was generally greater than 96% and 89% for cell lines and AML samples, respectively

Summary

Introduction

The hematopoietic system is a conglomerate of multiple lineages with the hematopoietic stem cell (HSC) as common origin [1]. In the BM, HSCs reside within a protective niche composed of an interconnected network of hematopoietic and non-hematopoietic cells that guide HSC quiescence, expansion, and homing [3]. Within non-hematopoietic cells, mesenchymal stromal cells (MSCs) are an essential niche element [7, 8]. MSCs are a well-characterized but heterogeneous population that resides in close proximity to the vasculature [9, 10] and expresses key hematopoietic factors such as stem cell factor (SCF) and stromal cell–derived factor 1 (SDF-1) [11, 12]. MSCs can give rise to other BM components of adipo-, osteo-, and chondrogenic lineage [7, 13] and de novo generate HSC- and AML-supportive extramedullary hematopoietic niches [14,15,16]

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Conclusion