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.
Highlights
Bcr-Abl fusion gene may be controlled by Bcr-Abl tyrosine kinase inhibitors (TKIs)
It has been reported that T cells specific for Chronic myelogenous leukemia (CML) cells develop in the patients, under certain therapies, which may lead to disease remission[18,19]
To investigate the effects of the Sipa1-deficient host environment on the CML-inducing activity of the primary BcrAbl+ hematopoietic progenitor cells (HPCs), we first transferred the primary lineage marker negative (Lin−) bone marrow (BM) cells from Wt B6 mice retrovirally transduced with p210Bcr-Abl into Wt and Sipa1−/− B6 mice intravenously at 1.5 × 104 cells/mouse according to the standard BM transplantation (BMT) procedure[34]
Summary
Bcr-Abl fusion gene may be controlled by Bcr-Abl tyrosine kinase inhibitors (TKIs). CML-initiating cells are resistant to TKIs and may persist as minimal residual disease. We demonstrate that mice deficient in Sipa[1], which encodes Rap[1] 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-deficient mice remain healthy for a year or so after birth, they may eventually develop diverse late-onset disorders in the immune and hematopoietic systems, including overt systemic autoimmunity and various hematological disorders with age[26,27,28] Such pleiotropic effects of Sipa[1] deficiency may be accounted for by the altered cellular interactions involved in the development of various lymphohematopoietic cell lineages in the unique tissue microenvironment[29]. Current results uncovered a novel mechanism potentially capable of eradicating Bcr-Abl+
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