A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML

Lanpeng Chen, Eline Pronk, Claire van Dijk, Yujie Bian, Jacqueline Feyen, Tim van Tienhoven, Meltem Yildirim, Paola Pisterzi, Madelon M.E. de Jong, Alejandro Bastidas, Remco M. Hoogenboezem, Chiel Wevers, Eric M. Bindels, Bob Löwenberg, Tom Cupedo, Mathijs A. Sanders, Marc H.G.P. Raaijmakers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
19 Downloads (Pure)

Abstract

Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted single-cell RNA sequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPC) 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 are predicted to repress high-output hematopoietic stem cell subsets in NPM1-mutated acute myeloid leukemia (AML), with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcomes 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.

Original languageEnglish
Pages (from-to)395-417
Number of pages23
JournalBlood cancer discovery
Volume4
Issue number5
DOIs
Publication statusPublished - 1 Sept 2023

Bibliographical note

Funding Information:
The authors wish to thank Nathalie Papazian and Michael Vermeulen for technical assistance, Mariette ter Borg for providing CD34+ cells; the HOVON/SAKK leukemia working group and all its members and participating sites for conducting the HOVON132 trial; Peter Valk, Patrycja Gradowska, and Jurjen Versluis for providing the genetic and clinical data; the Josephine Nefkens Precision Cancer Treatment Program for infrastructural support and members of the Erasmus MC Department of Hematology for providing scientific discussion and members of the Erasmus MC animal core facility EDC for help with animal care. This work was supported by grants from the Dutch Cancer Society (KWF Kankerbestrijding), Amsterdam, the Netherlands (grant EMCR 10488 and 11092 to M.H.G.P. Raaijmakers).

Funding Information:
Cancer Treatment Program for infrastructural support and members of the Erasmus MC Department of Hematology for providing scientific discussion and members of the Erasmus MC animal core facility EDC for help with animal care. This work was supported by grants from the Dutch Cancer Society (KWF Kankerbestrijding), Amsterdam, the Netherlands (grant EMCR 10488 and 11092 to M.H.G.P. Raaijmakers).

Publisher Copyright:
© 2023 The Authors.

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