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

doi:10.1158/2643-3230.BCD-23-0043

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

Hematology

Research output: Contribution to journal › Article › Academic › peer-review

14 Citations (Scopus)

52 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 language	English
Pages (from-to)	395-417
Number of pages	23
Journal	Blood cancer discovery
Volume	4
Issue number	5
DOIs	https://doi.org/10.1158/2643-3230.BCD-23-0043
Publication status	Published - 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/2643-3230.BCD-23-0043Licence: CC BY-NC-ND

A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AMLFinal published version, 21 MBLicence: CC BY-NC-ND

Cite this

Chen, L., Pronk, E., van Dijk, C., Bian, Y., Feyen, J., van Tienhoven, T., Yildirim, M., Pisterzi, P., de Jong, M. M. E., Bastidas, A., Hoogenboezem, R. M., Wevers, C., Bindels, E. M., Löwenberg, B., Cupedo, T., Sanders, M. A., & Raaijmakers, M. H. G. P. (2023). A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML. Blood cancer discovery, 4(5), 395-417. https://doi.org/10.1158/2643-3230.BCD-23-0043

@article{61aa5b5144904166ad968317fc93e807,

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

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.",

author = "Lanpeng Chen and Eline Pronk and {van Dijk}, Claire and Yujie Bian and Jacqueline Feyen and {van Tienhoven}, Tim and Meltem Yildirim and Paola Pisterzi and {de Jong}, {Madelon M.E.} and Alejandro Bastidas and Hoogenboezem, {Remco M.} and Chiel Wevers and Bindels, {Eric M.} and Bob L{\"o}wenberg and Tom Cupedo and Sanders, {Mathijs A.} and Raaijmakers, {Marc H.G.P.}",

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: {\textcopyright} 2023 The Authors.",

year = "2023",

month = sep,

day = "1",

doi = "10.1158/2643-3230.BCD-23-0043",

language = "English",

volume = "4",

pages = "395--417",

journal = "Blood cancer discovery",

issn = "2643-3230",

publisher = "NLM (Medline)",

number = "5",

}

Chen, L, Pronk, E, van Dijk, C, Bian, Y, Feyen, J, van Tienhoven, T, Yildirim, M, Pisterzi, P, de Jong, MME, Bastidas, A, Hoogenboezem, RM, Wevers, C, Bindels, EM , Löwenberg, B , Cupedo, T , Sanders, MA & Raaijmakers, MHGP 2023, 'A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML', Blood cancer discovery, vol. 4, no. 5, pp. 395-417. https://doi.org/10.1158/2643-3230.BCD-23-0043

TY - JOUR

T1 - A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML

AU - Chen, Lanpeng

AU - Pronk, Eline

AU - van Dijk, Claire

AU - Bian, Yujie

AU - Feyen, Jacqueline

AU - van Tienhoven, Tim

AU - Yildirim, Meltem

AU - Pisterzi, Paola

AU - de Jong, Madelon M.E.

AU - Bastidas, Alejandro

AU - Hoogenboezem, Remco M.

AU - Wevers, Chiel

AU - Bindels, Eric M.

AU - Löwenberg, Bob

AU - Cupedo, Tom

AU - Sanders, Mathijs A.

AU - Raaijmakers, Marc H.G.P.

N1 - 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.

PY - 2023/9/1

Y1 - 2023/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85169504081&partnerID=8YFLogxK

U2 - 10.1158/2643-3230.BCD-23-0043

DO - 10.1158/2643-3230.BCD-23-0043

M3 - Article

C2 - 37470778

AN - SCOPUS:85169504081

SN - 2643-3230

VL - 4

SP - 395

EP - 417

JO - Blood cancer discovery

JF - Blood cancer discovery

IS - 5

ER -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this