Deconvolution Of Hematopoietic Stem/Progenitor Cell Signaling Predicts Inflammatory Niche Remodeling To Be A Determinant Of Tissue Failure And Outcome In Human AML

  1. Lanpeng Chen
  2. Eline Pronk
  3. Claire van Dijk
  4. Yujie Bian
  5. Jacqueline Feyen
  6. Tim van Tienhoven
  7. Meltem Yildirim
  8. Paola Pisterzi
  9. Madelon de Jong
  10. Alejandro Bastidas
  11. Remco Hoogenboezem
  12. Chiel Wevers
  13. Eric Bindels
  14. Bob Löwenberg
  15. Tom Cupedo
  16. Mathijs A. Sanders
  17. Marc H.G.P. Raaijmakers
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Abstract

Cancer initiation is orchestrated by interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted scRNAsequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPCs) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR + stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors is predicted to repress distinct high-output HSC subsets in NPM1 -mutated AML, with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcome after chemotherapy, across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus, predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection, but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment.

statement of significance

Tumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcome in human AML.

Key points

  • A comprehensive taxonomy of the predicted interactions between LEPR + stromal niches, HSPCs and adaptive/innate immune cells in the human NBM.

  • Inflammation-associated decline of stromal niches in AML represses residual normal hematopoiesis with relative resistance of leukemic cells.

  • Inflammatory decline of stromal niches is associated with reduced relapse risk and favorable outcome.

Article activity feed

  1. Version published to 10.1101/2023.05.05.539525v1 on bioRxiv