Inducible expression of BCR/ABL using human CD34 regulatory elements results in a megakaryocytic myeloproliferative syndrome.
The BCR/ABL fusion protein is found in more than 90% of patients with chronic myeloid leukemia (CML) as well as in a subset of patients with acute B-cell leukemia. We have previously described a transgenic model for an inducible and reversible acute B-cell leukemia caused by p210 BCR/ABL. Here, we describe a new model of an inducible BCR/ABL disease by directing the expression of the oncogene to megakaryocytic progenitor cells within the murine bone marrow using the tetracycline-responsive expression system under the control of human CD34 regulatory elements. The predominant feature was the development of a chronic thrombocytosis. The condition progressed with the development of splenomegaly accompanied by lymphadenopathy in some mice. Affected animals demonstrated a dramatic increase in the number of megakaryocytes in the bone marrow and the spleen. Immunohistochemistry demonstrated that the reporter gene was expressed in hematopoietic stem cells (HSCs), common myeloid progenitor (CMP) cells, as well as in megakaryocytic/erythroid progenitor cells (MEPs). Although these mice did not display the increase in granulopoiesis commonly found in chronic myeloid leukemia (CML), the phenotype closely resembles a myeloproliferative disorder affecting the megakaryocytic lineage observed in some patients with the BCR/ABL P210 translocation.
Huettner
Claudia S
CS
Harvard Institutes of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Koschmieder
Steffen
S
Iwasaki
Hiromi
H
Iwasaki-Arai
Junko
J
Radomska
Hanna S
HS
Akashi
Koichi
K
Tenen
Daniel G
DG
D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics*; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D005809:Genes, Regulator / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008206:Lymphatic Diseases; D008533:Megakaryocytes / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D013163:Splenomegaly; D013752:Tetracycline / Q000494:pharmacology; D013922:Thrombocytosis
D018952:Antigens, CD34; D016044:Fusion Proteins, bcr-abl; D013752:Tetracycline