Journal Article

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

ster, Stefan, Nombela-Arrieta, César, Isringhausen, Stephan, Riether, Carsten, Amrein, Michael A, Schürch, Christian M, Ochsenbein, Adrian F, Brodie, Tess, Sayed, Mohamad Al, Zindel, Joel, Bührer, Elias D, Stroka, Deborah, Radpour, Ramin, Bhate, Salil S

2022

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Bone marrow / Chronic myeloid leukemia / Depletion / Disease resistance / Gene expression / Leukemia / Macrophages / Microenvironments / Myeloid leukemia / Progenitor cells / Red pulp / Spleen / Stem cell transplantation / Stem cells / Therapy