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

Yan Xu, Satoshi Ikeda, Kentaro Sumida, Ryusuke Yamamoto, Hiroki Tanaka and Nagahiro Minato ()
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Yan Xu: Kyoto University
Satoshi Ikeda: Kyoto University
Kentaro Sumida: Kyoto University
Ryusuke Yamamoto: Kyoto University
Hiroki Tanaka: Kyoto University
Nagahiro Minato: Kyoto University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03307-8

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