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Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells

Chronic myelogenous leukemia (CML) caused by hematopoietic stem cells expressing the Bcr-Abl fusion gene may be controlled by Bcr-Abl tyrosine kinase inhibitors (TKIs). However, CML-initiating cells are resistant to TKIs and may persist as minimal residual disease. We demonstrate that mice deficient...

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Detalles Bibliográficos
Autores principales: Xu, Yan, Ikeda, Satoshi, Sumida, Kentaro, Yamamoto, Ryusuke, Tanaka, Hiroki, Minato, Nagahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834470/
https://www.ncbi.nlm.nih.gov/pubmed/29500416
http://dx.doi.org/10.1038/s41467-018-03307-8
Descripción
Sumario:Chronic myelogenous leukemia (CML) caused by hematopoietic stem cells expressing the Bcr-Abl fusion gene may be controlled by Bcr-Abl tyrosine kinase inhibitors (TKIs). However, CML-initiating cells are resistant to TKIs and may persist as minimal residual disease. We demonstrate that mice deficient in Sipa1, which encodes Rap1 GTPase-activating protein, rarely develop CML upon transfer of primary hematopoietic progenitor cells (HPCs) expressing Bcr-Abl, which cause lethal CML disease in wild-type mice. Resistance requires both T cells and nonhematopoietic cells. Sipa1(−/−) mesenchymal stroma cells (MSCs) show enhanced activation and directed migration to Bcr-Abl(+) cells in tumor tissue and preferentially produce Cxcl9, which in turn recruits Sipa1(−/−) memory T cells that have markedly augmented chemotactic activity. Thus, Sipa1 deficiency uncovers a host immune mechanism potentially capable of eradicating Bcr-Abl(+) HPCs via coordinated interplay between MSCs and immune T cells, which may provide a clue for radical control of human CML.