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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4503-4510. Prepublished online as a Blood First Edition Paper on March 4, 2004; DOI 10.1182/blood-2003-09-3262. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-09-3262v1 103/12/4503    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Moody, J. L. Articles by Jirik, F. R. Search for Related Content PubMed PubMed Citation Articles by Moody, J. L. Articles by Jirik, F. R. Related Collections Hematopoiesis and Stem Cells Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Anemia, thrombocytopenia, leukocytosis, extramedullary hematopoiesis, and impaired progenitor function in Pten+/-SHIP-/- mice: a novel model of myelodysplasia Jennifer L. Moody, Lixin Xu, Cheryl D. Helgason, and Frank R. Jirik From the Department of Biochemistry and Molecular Biology, University of Calgary, AB, Canada; and the Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, BC, Canada. The myeloproliferative disorder of mice lacking the Src homology 2 (SH2)-containing 5' phosphoinositol phosphatase, SHIP, underscores the need for closely regulating phosphatidylinositol 3-kinase (PI3K) pathway activity, and hence levels of phosphatidylinositol species during hematopoiesis. The role of the 3' phosphoinositol phosphatase Pten in this process is less clear, as its absence leads to embryonic lethality. Despite Pten heterozygosity being associated with a lymphoproliferative disorder, we found no evidence of a hematopoietic defect in Pten+/- mice. Since SHIP shares the same substrate (PIP3) with Pten, we hypothesized that the former might compensate for Pten haploinsufficiency in the marrow. Thus, we examined the effect of Pten heterozygosity in SHIP-/- mice, predicting that further dysregulation of PIP3 metabolism would exacerbate the pheno-type of the latter. Indeed, compared with SHIP-/- mice, Pten+/-SHIP-/- animals developed a myelodysplastic phenotype characterized by increased hepatosplenomegaly, extramedullary hematopoiesis, anemia, and thrombocytopenia. Consistent with a marrow defect, clonogenic assays demonstrated reductions in committed myeloid and megakaryocytic progenitors in these animals. Providing further evidence of a Pten+/-SHIP-/- progenitor abnormality, reconstitution of irradiated mice with marrows from these mice led to a marked defect in short-term repopulation of peripheral blood by donor cells. These studies suggest that the regulation of the levels and/or ratios of PI3K-derived phosphoinositol species by these 2 phosphatases is critical to normal hematopoiesis. (Blood. 2004;103:4503-4510) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Myeloproliferation or dysplasia: a matter of PIP3 levels? Hanno Glimm Blood 2004 103: 4378. [Full Text] [PDF] This article has been cited by other articles: S. Costinean, S. K. Sandhu, I. M. Pedersen, E. Tili, R. Trotta, D. Perrotti, D. Ciarlariello, P. Neviani, J. Harb, L. R. Kauffman, et al. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein {beta} are targeted by miR-155 in B cells of E{micro}-MiR-155 transgenic mice Blood, August 13, 2009; 114(7): 1374 - 1382. [Abstract] [Full Text] [PDF] M. Heuser, D. B. Yap, M. Leung, T. R. de Algara, A. Tafech, S. McKinney, J. Dixon, R. Thresher, B. Colledge, M. Carlton, et al. Loss of Mll5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation Blood, February 12, 2009; 113(7): 1432 - 1443. [Abstract] [Full Text] [PDF] D. W. Lee, Q.-S. Zhu, S. Rudra, E. J. Shpall, S. Kornblau, and S. J. Corey Abnormal PI 3-Kinase Activity Due to Increased Lyn with Decreased PTEN and Absent SHIP in Bone Marrow Cells from Patients with Myelodysplastic Syndromes. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 3446 - 3446. [Abstract] Y.-W. Lin, C. Slape, Z. Zhang, and P. D. Aplan NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia Blood, July 1, 2005; 106(1): 287 - 295. [Abstract] [Full Text] [PDF] D. W. Lee, Q.-S. Zhu, G. Zamora, O. Nwawka, E. J. Shpall, S. K. Kornblau, and S. J. Corey Disturbed Regulation and Activity of PI 3-Kinase Activity Due to Enhanced Lyn Kinase but Decreased Ship-1 and Gab2 Levels in Patients with Myelodysplastic Syndrome. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 3423 - 3423. [Abstract]

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