Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia.
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Embargo End Date
ICR Authors
Authors
Waclawiczek, A
Hamilton, A
Rouault-Pierre, K
Abarrategi, A
Albornoz, MG
Miraki-Moud, F
Bah, N
Gribben, J
Fitzgibbon, J
Taussig, D
Bonnet, D
Hamilton, A
Rouault-Pierre, K
Abarrategi, A
Albornoz, MG
Miraki-Moud, F
Bah, N
Gribben, J
Fitzgibbon, J
Taussig, D
Bonnet, D
Document Type
Journal Article
Date
2020-06-01
Date Accepted
2020-02-26
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.
Citation
The Journal of clinical investigation, 2020, 130 (6), pp. 3038 - 3050
Source Title
Publisher
AMER SOC CLINICAL INVESTIGATION INC
ISSN
0021-9738
eISSN
1558-8238
1558-8238
1558-8238
Collections
Research Team
Acute Leukaemia