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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4664-4670. Prepublished online as a Blood First Edition Paper on March 1, 2005; DOI 10.1182/blood-2005-01-0050. This Article Full Text (PDF) All Versions of this Article: 2005-01-0050v1 105/12/4664    most recent Alert me when this article is cited Alert me if a correction is posted 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 Heller, P. G Articles by Molinas, F. C Search for Related Content PubMed PubMed Citation Articles by Heller, P. G Articles by Molinas, F. C Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 6, 2005 Accepted February 4, 2005 Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation Paula G Heller*, Ana C Glembotsky, Manish J Gandhi, Carrie L Cummings, Carlos J Pirola, Rosana F Marta, Laura I Kornblihtt, Jonathan G Drachman, and Felisa C Molinas Division of Hematology, Insitituto de Investigaciones Medicas Alfredo Lanari, University of Buenos Aires, Buenos Aires, Argentina Puget Sound Blood Center, Seattle, WA, USA; Division of Hematology, University of Washington, Seattle, WA, USA Puget Sound Blood Center, Seattle, WA, USA Division of Molecular Cardiology, Instituto de Investigaciones Medicas Alfredo Lanari, University of Buenos Aires, Buenos Aires, Argentina * Corresponding author; email: idimhematologia{at}hotmail.com. Germ-line heterozygous mutations in the hematopoietic transcription factor AML1 have been identified in patients with familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML), which is characterized by thrombocytopenia, abnormal platelet function and propensity to myeloid malignancies. We identified a novel mutation in the AML1 gene in a FPD/AML pedigree characterized by a single nucleotide deletion that generates a frameshift and premature chain termination (Pro218fs-Ter225). Both wild-type and mutant transcripts were expressed in affected individuals by allele-specific RT-PCR. Thrombopoietin (TPO) binds to the Mpl receptor and is the major regulator of megakaryopoiesis. To explore the mechanisms underlying thrombocytopenia, we studied the TPO/Mpl pathway in this newly identified pedigree. TPO levels were mildly to moderately elevated. On flow cytometry and immunoblotting, Mpl receptor expression was decreased and TPO-induced signaling was impaired. While no mutations were identified in the MPL gene by sequence analysis, low MPL mRNA levels were found, suggesting decreased gene expression. Of particular interest, several AML1-binding motifs are present in the MPL promoter, suggesting MPL is an AML1-target. In conclusion, we identified a C-terminal AML1 mutation that leads to a decrease in Mpl receptor expression, providing a potential explanation for thrombocytopenia in this FPD/AML pedigree. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Decreased platelet Mpl receptor in AML1 haplodeficiency: another piece of the puzzle A. Koneti Rao Blood 2005 105: 4545. [Full Text] [PDF] This article has been cited by other articles: C. J. Owen, C. L. Toze, A. Koochin, D. L. Forrest, C. A. Smith, J. M. Stevens, S. C. Jackson, M.-C. Poon, G. D. Sinclair, B. Leber, et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy Blood, December 1, 2008; 112(12): 4639 - 4645. [Abstract] [Full Text] [PDF] Y. Satoh, I. Matsumura, H. Tanaka, S. Ezoe, K. Fukushima, M. Tokunaga, M. Yasumi, H. Shibayama, M. Mizuki, T. Era, et al. AML1/RUNX1 Works as a Negative Regulator of c-Mpl in Hematopoietic Stem Cells J. Biol. Chem., October 31, 2008; 283(44): 30045 - 30056. [Abstract] [Full Text] [PDF] K. Kirito, K. Sakoe, D. Shinoda, Y. Takiyama, K. Kaushansky, and N. Komatsu A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies Haematologica, January 1, 2008; 93(1): 155 - 156. [Abstract] [Full Text] [PDF] A. Savoia, C. Dufour, F. Locatelli, P. Noris, C. Ambaglio, V. Rosti, M. Zecca, S. Ferrari, F. di Bari, A. Corcione, et al. Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations Haematologica, September 1, 2007; 92(9): 1186 - 1193. [Abstract] [Full Text] [PDF] L. Petit-Cocault, C. Volle-Challier, M. Fleury, B. Peault, and M. Souyri Dual role of Mpl receptor during the establishment of definitive hematopoiesis Development, August 15, 2007; 134(16): 3031 - 3040. [Abstract] [Full Text] [PDF] T. Katsumoto, Y. Aikawa, A. Iwama, S. Ueda, H. Ichikawa, T. Ochiya, and I. Kitabayashi MOZ is essential for maintenance of hematopoietic stem cells. Genes & Dev., May 15, 2006; 20(10): 1321 - 1330. [Abstract] [Full Text] [PDF] V. Hamelin, C. Letourneux, P.-H. Romeo, F. Porteu, and M. Gaudry Thrombopoietin regulates IEX-1 gene expression through ERK-induced AML1 phosphorylation Blood, April 15, 2006; 107(8): 3106 - 3113. [Abstract] [Full Text] [PDF]

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