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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.

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