MSC-expressed CXCL12 promotes LSC quiescence and promotes BCR–ABL inhibitor resistance.
Major Finding: MSC-expressed CXCL12 promotes LSC quiescence and promotes BCR–ABL inhibitor resistance.
Concept: Specific niche cell types in the bone marrow enhance LSC self-renewal, quiescence, and TKI sensitivity.
Impact: CXCL12+ MSC niches may be potential targets for enhancing TKI sensitivity.
The chemokine CXCL12 plays a major role in the intricate hematopoietic stem cell (HSC) regulation, and it is expressed by a wide range of cell types with potential niche function in the bone marrow. Although niche perturbations are a common observation in chronic myeloid leukemia (CML), their mechanistic relevance to disease pathogenesis and treatment response is still unclear. Using Cre recombinase transgenic mouse lines targeting specific cell types of the HSC niche, Agarwal and colleagues identified a specific supporting role for mesenchymal stromal cell (MSC)–expressed CXCL12 in maintaining the functionality of both normal and leukemic hematopoietic stem cells. They transplanted normal bone marrow or leukemic marrow (derived from BCR–ABL-expressing transgenic mice) into mice with CXCL2-deficient HSC niches, where Cxcl12 was depleted in either endothelial cells (using Tek-Cre), MSCs (using Prx1-Cre), or osteoblasts (using Osx-Cre or Ocn-Cre). Cxcl12 loss specifically in MSC, but not other niches, impaired normal HSC functionality in transplantation assays, and Cxcl2 deletion in endothelial cells suppressed leukemic stem cell (LSC) proliferation. However, Cxcl12 deletion in MSCs markedly reduced quiescence of BCR–ABL+ LSCs, increased LSC self-renewal capacity, and significantly enhanced LSC engraftment post-transplantation. RNA-sequencing analysis confirmed that LSCs from Prx1-Cre+ Cxcl12f/f mice showed significant downregulation of TGFβ and STAT3 gene sets, which are key regulators of LSC quiescence and TKI persistence in BCR–ABL+ CML, and upregulation of EZH2 expression and PRC2 activity, which are key regulators of stem-cell proliferation and self-renewal. This study finds that CML LSCs, unlike normal HSCs, colocalize to abnormal clusters of MSC that are lost upon deletion of MSC-expressed CXCL12 with increase in their long-term engraftment and self-renewal capacity. However, this comes at a cost—CXCL12 deletion from MSCs sensitized LSCs to the second-generation BCR–ABL TKI nilotinib. This observation of a niche-specific LSC dependency supports further explorations of LSC-promoting factors in the CML LSC niche that could serve as potential targets for therapeutic intervention.
Agarwal P, Isringhausen S, Li H, Paterson AJ, He J, Gomariz Á, et al. Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells. Cell Stem Cell 2019 Mar 14 [Epub ahead of print].
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