||Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells
Xu, Yan ,
Ikeda, Satoshi ,
Sumida, Kentaro ,
Yamamoto, Ryusuke ,
Tanaka, HirokiMinato, Nagahiro
92018-03-02 , Springer Nature
がん免疫の束縛を解く --白血病を拒絶する新しい免疫機構--. 京都大学プレスリリース. 2018-03-06.
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.