Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance.

Bührer, Elias D; Amrein, Michael A; Forster, Stefan; Isringhausen, Stephan; Schürch, Christian M; Bhate, Salil S; Brodie, Tess; Zindel, Joel; Stroka, Deborah; Al Sayed, Mohamad; Nombela-Arrieta, César; Radpour, Ramin; Riether, Carsten; Ochsenbein, Adrian F (2022). Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance. Leukemia, 36(11), pp. 2634-2646. Springer Nature 10.1038/s41375-022-01682-2

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Disease progression and relapse of chronic myeloid leukemia (CML) are caused by therapy resistant leukemia stem cells (LSCs), and cure relies on their eradication. The microenvironment in the bone marrow (BM) is known to contribute to LSC maintenance and resistance. Although leukemic infiltration of the spleen is a hallmark of CML, it is unknown whether spleen cells form a niche that maintains LSCs. Here, we demonstrate that LSCs preferentially accumulate in the spleen and contribute to disease progression. Spleen LSCs were located in the red pulp close to red pulp macrophages (RPM) in CML patients and in a murine CML model. Pharmacologic and genetic depletion of RPM reduced LSCs and decreased their cell cycling activity in the spleen. Gene expression analysis revealed enriched stemness and decreased myeloid lineage differentiation in spleen leukemic stem and progenitor cells (LSPCs). These results demonstrate that splenic RPM form a niche that maintains CML LSCs in a quiescent state, resulting in disease progression and resistance to therapy.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Bührer, Elias; Amrein, Michael Alex; Forster, Stefan; Schürch, Christian; Brodie, Tess Melinda; Zindel, Joel; Keogh-Stroka, Deborah M.; Al Sayed, Mohamad; Radpour, Ramin; Riether, Carsten and Ochsenbein, Adrian

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1476-5551

Publisher:

Springer Nature

Language:

English

Submitter:

Pubmed Import

Date Deposited:

29 Sep 2022 09:22

Last Modified:

05 Dec 2022 16:25

Publisher DOI:

10.1038/s41375-022-01682-2

PubMed ID:

36163264

BORIS DOI:

10.48350/173353

URI:

https://boris.unibe.ch/id/eprint/173353

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