Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice

Ishida, Daisuke; Kometani, Kohei; Yang, Hailin; Kakugawa, Kiyokazu; Masuda, Kyoko; Iwaï, Kazuhiro; Suzuki, Misao; Itohara, Shigeyoshi; Nakahata, Tatsutoshi; Hayashi, Hiroshi; Kawamoto, Hiroshi; Hattori, Masao; Minato, Nagahiro

doi:10.1016/s1535-6108(03)00163-6

Cited by 118 publications

(143 citation statements)

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“…1 A). Ninety-five percent of SPA-1 Ϫ/Ϫ mice developed myeloid disorders by 16 months, with the initial signs becoming evident after 12 months (18). In the present cohort, SPA-1 Ϫ/Ϫ mice of various ages that showed no sign of the myeloid diseases by blood analysis and autopsies until 12 months and rare three 16-month-old mice without the diseases were used.…”

Section: Resultsmentioning

confidence: 99%

“…E14 embryonic stem cells were transfected with a linearized SPA-1 gene-targeting vector, in which a region covering exons 5-8 was replaced by a 1.8-kb fragment containing a pgk-neo cassette, microinjected into C57BL͞6 (B6) blastocysts, and the resulting chimeras were mated with B6 mice (18). Heterozygous offspring were intercrossed to produce homozygous mutant mice, and those with mixed genetic backgrounds were used.…”

Section: Methodsmentioning

confidence: 99%

“…SPA-1 is a predominant Rap1GAP expressed in the lymphohematopoietic tissues (16,17). Recently, we generated SPA-1 gene-deficient (SPA-1 Ϫ/Ϫ ) mice and found that they developed a spectrum of myeloid disorders that resembled human chronic myelogenous leukemia in the chronic phase, chronic myelogenous leukemia in blast crisis, or myelodysplastic syndrome (18). In the present study, we show that preceding the development of myeloid disorders, SPA-1 Ϫ/Ϫ mice develop an age-dependent progression of T cell unresponsiveness due to the antigen-driven increase in anergic T cells with large amounts of Rap1GTP.…”

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confidence: 99%

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Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice

Ishida

Yang²,

Masuda³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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SPA-1 is a principal Rap1 GTPase-activating protein in the hematopoietic progenitors and peripheral T cells, and SPA-1-deficient mice develop a spectrum of myeloproliferative stem cell disorders of late onset. In the present study, we show that SPA-1-deficient mice develop age-dependent T cell unresponsiveness preceding the myeloid disorders, whereas the T cell numbers remained unchanged. Progression of the T cell dysfunction was attributed to the age-dependent increase in CD44 high T cell population that was unresponsive to T cell receptor stimulation. Younger SPA-1-deficient mice exhibited selectively impaired recall T cell responses against a T-dependent antigen with normal primary antibody response. These results suggested that the unresponsiveness of CD44 high T cells was antigen-driven in vivo. T cells from younger SPA-1 ؊/؊ mice showed much greater and more persisted Rap1 activation by anti-CD3 stimulation than control T cells. Furthermore, freshly isolated T cells from SPA-1 ؊/؊ mice exhibited progressive accumulation of Rap1GTP as mice aged. T cells from aged SPA-1 ؊/؊ mice with high amounts of Rap1GTP showed normal or even enhanced Ras activation with little extracellular signal-regulated kinase activation in response to anti-CD3 stimulation, indicating that excess Rap1GTP induced the uncoupling of Ras-mediated extracellular signal-regulated kinase activation. These results suggested that antigenic activation of naïve T cells in SPA-1 ؊/؊ mice was followed by anergic rather than memory state due to the defective down-regulation of Rap1 activation, resulting in the age-dependent progression of overall T cell immunodeficiency.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice

Ishida

Yang²,

Masuda³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Both bone marrow preleukemic progenitors and overt leukemic blast cells in SPA-1/ mice showed markedly increased Rap1GTP levels, accompanied by a constitutive ERK activation. It was further demonstrated that the retroviral transduction of an activated mutant of Rap1, RapE63, into the normal bonemarrow progenitors significantly enhanced their expansion, whereas the overexpression of SPA-1 strongly suppressed it, confirming a positive role of Rap1 in proliferation of hematopoietic progenitors (Ishida et al, 2003). Intriguingly, in a leukemic cell line established from a SPA-1 deficient mouse with the disorder resembling CML in blast crisis, SPA-1 did not significantly affect the constitutive Erk activation and the proliferation rate, which were most likely due to constitutive activation of Ras, but abrogated the leukemogenic activity in vivo.…”

Section: Rap1 Activation By Bcr/abl and Il-3mentioning

confidence: 91%

“…Most significantly, it was found that SPA-1-deficient mice developed myeloproliferative disorders resembling CML in chronic phase and in blast crisis (Ishida et al, 2003). Both bone marrow preleukemic progenitors and overt leukemic blast cells in SPA-1/ mice showed markedly increased Rap1GTP levels, accompanied by a constitutive ERK activation.…”

Section: Rap1 Activation By Bcr/abl and Il-3mentioning

confidence: 99%

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

et al. 2006

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Models for Human Leukaemias

Koschmieder

2007

The Cancer Handbook

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Animal models for human leukaemias have provided important insight into their molecular pathogenesis. As a consequence, molecularly targeted therapy for several human leukaemias has entered clinical practice, which greatly improves efficacy and lowers toxicity of anti‐leukaemic treatment. Several organisms are being utilized to study the process of leukaemic transformation, including not only Drosophila , Caenorhabditis elegans , or Xenopus but also zebrafish. Most frequently though, spontaneous or induced leukaemias in the mouse are used. Using xenotransplant models of human leukaemic cell lines and leukaemic cells from patients into immunodeficient mouse strains, we have learnt important lessons about the composition of the leukaemic cell population in human disease. In fact, these experiments led to the description of leukaemia‐initiating cells, the first described cancer stem cell. However, animal models have also led to the definition of oncogenes required for leukaemic transformation and are also being used for the evaluation of molecular therapeutic targets. Two strategies for the evaluation of genes in the pathogenesis of human leukaemias are frequently used: (i) transplantation strategies, where genetically modified cell lines or primary bone marrow is injected into recipient animals. (ii) Analyses of genetically modified animals. Both model systems have led to important insights into the role of human oncogenes in leukaemic transformation. Most recently, these model systems are combined to yield sophisticated information about the cooperation of oncogenes, to identify genes that are important for abnormal stem cell functions, and to evaluate the oncogene products as therapeutic targets.

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Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice

Cited by 118 publications

References 50 publications

Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice

Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

Models for Human Leukaemias

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