The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission
| Autor: | Jeanpierre, Sandrine, Arizkane, Kawtar, Thongjuea, Supat, Grockowiak, Elodie, Geistlich, Kevin, Barral, Lea, Voeltzel, Thibault, Guillemin, Anissa, Gonin-Giraud, Sandrine, Gandrillon, Olivier, Nicolini, Franck-Emmanuel, Mead, Adam, Maguer-Satta, Veronique, Lefort, Sylvain |
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| Přispěvatelé: | Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), maguer-satta, veronique, École normale supérieure de Lyon (ENS de Lyon) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
STAT3 Transcription Factor
education Fusion Proteins bcr-abl [SDV.CAN]Life Sciences [q-bio]/Cancer Bone Morphogenetic Protein 4 Hematopoietic Stem Cells Article [SDV.CAN] Life Sciences [q-bio]/Cancer hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive Neoplastic Stem Cells Tumor Microenvironment Humans Protein Kinase Inhibitors Bone Morphogenetic Protein Receptors Type I |
| Zdroj: | Haematologica Haematologica, Ferrata Storti Foundation, 2020, pp.haematol.2019.232793. ⟨10.3324/haematol.2019.232793⟩ Haematologica, 2020, pp.haematol.2019.232793. ⟨10.3324/haematol.2019.232793⟩ |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.2019.232793⟩ |
| Popis: | Chronic myelogenous leukemia arises from the transformation of hematopoietic stem cells by the BCR-ABL oncogene. Though transformed cells are predominantly BCR-ABL-dependent and sensitive to tyrosine kinase inhibitor treatment, some BMPR1B+ leukemic stem cells are treatment-insensitive and rely, among others, on the bone morphogenetic protein (BMP) pathway for their survival via a BMP4 autocrine loop. Here, we further studied the involvement of BMP signaling in favoring residual leukemic stem cell persistence in the bone marrow of patients having achieved remission under treatment. We demonstrate by single-cell RNA-Seq analysis that a sub-fraction of surviving BMPR1B+ leukemic stem cells are co-enriched in BMP signaling, quiescence and stem cell signatures, without modulation of the canonical BMP target genes, but enrichment in actors of the Jak2/Stat3 signaling pathway. Indeed, based on a new model of persisting CD34+CD38- leukemic stem cells, we show that BMPR1B+ cells display co-activated Smad1/5/8 and Stat3 pathways. Interestingly, we reveal that only the BMPR1B+ cells adhering to stromal cells display a quiescent status. Surprisingly, this quiescence is induced by treatment, while non-adherent BMPR1B+ cells treated with tyrosine kinase inhibitors continued to proliferate. The subsequent targeting of BMPR1B and Jak2 pathways decreased quiescent leukemic stem cells by promoting their cell cycle re-entry and differentiation. Moreover, while Jak2-inhibitors alone increased BMP4 production by mesenchymal cells, the addition of the newly described BMPR1B inhibitor (E6201) impaired BMP4-mediated production by stromal cells. Altogether, our data demonstrate that targeting both BMPR1B and Jak2/Stat3 efficiently impacts persisting and dormant leukemic stem cells hidden in their bone marrow microenvironment. |
| Databáze: | OpenAIRE |
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