A Gremlin 1-expressing splenic niche cell population restrains chronic myeloid leukemia by antagonizing the BMP pathway

Sawyers, C. L. Chronic myeloid leukemia. N. Engl. J. Med. 340, 1330–1340 (1999).

Article  CAS  PubMed  Google Scholar 

Holyoake, T. L. & Vetrie, D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood 129, 1595–1606 (2017).

Article  CAS  PubMed  Google Scholar 

Houshmand, M. et al. Chronic myeloid leukemia stem cells. Leukemia 33, 1543–1556 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Duarte, D., Hawkins, E. D. & Lo Celso, C. The interplay of leukemia cells and the bone marrow microenvironment. Blood 131, 1507–1511 (2018).

Article  CAS  PubMed  Google Scholar 

Medyouf, Hind The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications. Blood 129, 1617–1626 (2017).

Article  CAS  PubMed  Google Scholar 

Schepers, K., Campbell, T. B. & Passegué, E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell 16, 254–267 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, B. et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21, 577–592 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Agarwal, P. et al. Mesenchymal niche-specific expression of CXCL12 controls quiescence of treatment-resistant leukemia stem cells. Cell Stem Cell 24, 769–784 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Laperrousaz, B. et al. Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression. Blood 122, 3767–3777 (2013).

Article  CAS  PubMed  Google Scholar 

Zhang, B. et al. Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nat. Med. 24, 450–462 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Faderl, S. et al. The biology of chronic myeloid leukemia. N. Engl. J. Med. 341, 164–172 (1999).

Article  CAS  PubMed  Google Scholar 

McKenzie, C. V., Colonne, C. K., Yeo, J. H. & Fraser, S. T. Splenomegaly: pathophysiological bases and therapeutic options. Int. J. Biochem. Cell Biol. 94, 40–43 (2018).

Article  CAS  PubMed  Google Scholar 

Jabbour, E. & Kantarjian, H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am. J. Hematol. 93, 442–459 (2018).

Article  PubMed  Google Scholar 

Mesa, R. A., Elliott, M. A. & Tefferi, A. Splenectomy in chronic myeloid leukemia and myelofibrosis with myeloid metaplasia. Blood Rev. 14, 121–129 (2000).

Article  CAS  PubMed  Google Scholar 

Schemionek, M. et al. Leukemic spleen cells are more potent than bone marrow-derived cells in a transgenic mouse model of CML. Leukemia 26, 1030–1037 (2012).

Article  CAS  PubMed  Google Scholar 

Dutta, P. et al. Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. J. Exp. Med. 212, 497–512 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Inra, C. N. et al. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527, 466–471 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Khokha, M. K., Hsu, D., Brunet, L. J., Dionne, M. S. & Harland, R. M. Gremlin is the BMP antagonist required for maintenance of SHH and FGF signals during limb patterning. Nat. Genet. 34, 303–307 (2003).

Article  CAS  PubMed  Google Scholar 

Davis, H. et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 21, 62–70 (2015).

Article  CAS  PubMed  Google Scholar 

Yan, K. et al. Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy. Genes Dev. 28, 1085–1100 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cheng, C. et al. Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer. Nat. Cancer 3, 565–580 (2022).

Article  CAS  PubMed  Google Scholar 

Worthley, D. L. et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160, 269–284 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kapoor, V. N. et al. Gremlin 1+ fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues. Nat. Immunol. 22, 571–585 (2021).

Article  CAS  PubMed  Google Scholar 

Koschmieder, S. et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR–ABL leukemogenesis. Blood 105, 324–334 (2005).

Article  CAS  PubMed  Google Scholar 

Ren, J. et al. Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer progression. Breast Cancer Res. 21, 109 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Chang, S. H. et al. Excessive mechanical loading promotes osteoarthritis through the Gremlin-1–NF-κB pathway. Nat. Commun. 10, 1442 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Schmidt, S. F. et al. Acute TNF-induced repression of cell identity genes is mediated by NFκB-directed redistribution of cofactors from super-enhancers. Genome Res. 25, 1281–1294 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schemionek, M. et al. BCR–ABL enhances differentiation of long-term repopulating hematopoietic stem cells. Blood 115, 3185–3195 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bührer, E. D. et al. Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance. Leukemia 36, 2634–2646 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Alexandre, Y. O. et al. A diverse fibroblastic stromal cell landscape in the spleen directs tissue homeostasis and immunity. Sci. Immunol. 7, eabj0641 (2022).

Article  CAS  PubMed  Google Scholar 

Cheng, H.-W. et al. Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp. Nat. Commun. 10, 1739 (2019).

Article  PubMed 

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