10779/crick.12472751.v1
Alexander Waclawiczek
Alexander
Waclawiczek
Ashley Hamilton
Ashley
Hamilton
Kevin Rouault-Pierre
Kevin
Rouault-Pierre
Ander Abarrategi
Ander
Abarrategi
Manuel Garcia Albornoz
Manuel Garcia
Albornoz
Farideh Miraki-Moud
Farideh
Miraki-Moud
Nourdine Bah
Nourdine
Bah
John Gribben
John
Gribben
Jude Fitzgibbon
Jude
Fitzgibbon
David Taussig
David
Taussig
Dominique Bonnet
Dominique
Bonnet
Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia.
The Francis Crick Institute
2020
Adult stem cells
Hematology
Hematopoietic stem cells
Leukemias
Stem cells
Bonnet FC001045
CB
Immunology
11 Medical and Health Sciences
2020-06-25 14:05:31
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Mesenchymal_niche_remodeling_impairs_hematopoiesis_via_stanniocalcin_1_in_acute_myeloid_leukemia_/12472751
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.