Somatic activation of a conditional KrasG12D allele causes ineffective erythropoiesis in vivo

Somatic activation of a conditional targeted KrasG12D allele induces a fatal myeloproliferative disease in mice that closely models juvenile and chronic myelomonocytic leukemia. These mice consistently develop severe and progressive anemia despite adequate numbers of clonogenic erythroid progenitors...

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Published inBlood Vol. 108; no. 6; pp. 2041 - 2044
Main Authors Braun, Benjamin S., Archard, Joehleen A., Van Ziffle, Jessica A.G., Tuveson, David A., Jacks, Tyler E., Shannon, Kevin
Format Journal Article
LanguageEnglish
Published Washington, DC Elsevier Inc 15.09.2006
The Americain Society of Hematology
The American Society of Hematology
Subjects
Alleles
Anemia - blood
Anemia - etiology
Anemia - genetics
Anemia - pathology
Animals
Biological and medical sciences
Erythropoiesis - genetics
Gene Expression Regulation
Genes, ras
Hematologic and hematopoietic diseases
Humans
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Myelodysplastic Syndromes - genetics
Myeloproliferative Disorders - genetics
Neoplasia
Myelomonocytic leukemia
Animal model
Ineffective erythropoiesis
Anemia
Rodentia
Malignant hemopathy
K ras Gene
In vivo
Vertebrata
Allele
Mammalia
Mouse
Animal
Bone marrow
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Summary:Somatic activation of a conditional targeted KrasG12D allele induces a fatal myeloproliferative disease in mice that closely models juvenile and chronic myelomonocytic leukemia. These mice consistently develop severe and progressive anemia despite adequate numbers of clonogenic erythroid progenitors in the bone marrow and expanded splenic hematopoiesis. Ineffective erythropoiesis is characterized by impaired differentiation. These results demonstrate that endogenous levels of oncogenic Ras have cell lineage-specific effects and support efforts to modulate Ras signaling for therapy of anemia in patients with myelodysplastic syndromes and myeloproliferative disorders.
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Supported in part by National Institutes of Health grants K08 CA103868, R01 CA72614, and P30 CA082103, and by the Frank A. Campini Foundation.
The online version of this article contains a data supplement.
Reprints: Kevin M. Shannon, Department of Pediatrics, HSE-302, Box 0519, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143; e-mail: shannonk@peds.ucsf.edu.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.
B.S.B. designed the experiment, performed research, and wrote the manuscript; J.A.A. maintained the mice and performed research; J.A.V.Z. designed the experiment and performed research; D.A.T. and T.E.J. developed the transgenic mice; K.S. designed the experiment and wrote the manuscript.
Prepublished online as Blood First Edition Paper, May 23, 2006; DOI 10.1182/blood-2006-01-013490.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2006-01-013490