Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells.
Nat Commun
; 9(1): 914, 2018 03 02.
Article
em En
| MEDLINE
| ID: mdl-29500416
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
/
Proteínas Nucleares
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Proteínas Ativadoras de GTPase
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article