Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia. 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 10779/crick.12472751.v1 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. 2020-06-25 14:05:31 Adult stem cells Hematology Hematopoietic stem cells Leukemias Stem cells Bonnet FC001045 CB Immunology 11 Medical and Health Sciences