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

被引：13

作者：

Buhrer, Elias D. ^{[1
,2
,3
]}

Amrein, Michael A. ^{[1
,2
,3
]}

Forster, Stefan ^{[1
,2
,3
]}

Isringhausen, Stephan ^{[4
,5
]}

Schuerch, Christian M. ^{[6
,7
,8
,9
,10
]}

Bhate, Salil S. ^{[7
]}

Brodie, Tess ^{[11
]}

Zindel, Joel ^{[11
]}

Stroka, Deborah ^{[11
]}

Al Sayed, Mohamad ^{[1
,2
]}

Nombela-Arrieta, Cesar ^{[4
,5
]}

Radpour, Ramin ^{[1
,2
]}

Riether, Carsten ^{[1
,2
]}

Ochsenbein, Adrian F. ^{[1
,2
]}

机构：

[1] Univ Bern, Bern Univ Hosp, Inselspital, Dept Med Oncol, Bern, Switzerland

[2] Univ Bern, Dept BioMed Res, Tumor Immunol, Bern, Switzerland

[3] Univ Bern, Grad Sch Cellular & Biomed Sci, Bern, Switzerland

[4] Univ Hosp Zurich, Dept Med Oncol & Hematol, Zurich, Switzerland

[5] Univ Zurich, Zurich, Switzerland

[6] Univ Bern, Inst Pathol, Bern, Switzerland

[7] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA USA

[8] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[9] Univ Hosp, Dept Pathol & Neuropathol, Tubingen, Germany

[10] Comprehens Canc Ctr Tubingen, Tubingen, Germany

[11] Univ Bern, Dept BioMed Res, Visceral Surg, Bern, Switzerland

来源：

LEUKEMIA | 2022年 / 36卷 / 11期

基金：

瑞士国家科学基金会;

关键词：

CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITORS; BONE-MARROW NICHE; PROGENITOR CELLS; MOUSE MODEL; GM-CSF; MICROENVIRONMENT; DIFFERENTIATION; SPLENECTOMY; IRRADIATION;

D O I：

10.1038/s41375-022-01682-2

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2634 / 2646

页数：13

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