Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Philadelphia (Ph) chromosome can be detected in chronic myelogenous leukemia (CML) and a significant number of acute lymphoblastic leukemia (ALL) cases. Generation of p210bcr/abl, a chimeric protein with enhanced kinase activity, is thought to be involved in the pathogenesis of these diseases. To elucidate the biological properties of p210bcr/abl and to create an animal model for human Ph1-positive leukemias, we generated transgenic mice expressing p210bcr/abl driven by the promoter of the tec gene, a cytoplasmic tyrosine-kinase preferentially expressed in the hematopoietic lineage. The founder mice showed excessive proliferation of lymphoblasts shortly after birth and were diagnosed as suffering from ALL based on surface marker and Southern blot analyses. Expression and enhanced kinase activity of the p210bcr/abl transgene product were detected in the leukemic tissues. In contrast, transgenic progeny exhibited marked granulocyte hyperplasia with thrombocytosis after a long latent period and developed myeloproliferative disorders (MPDs) closely resembling human CML. Expression of p210(bcr/abl) mRNA in the proliferating granulocytes was detected by RT-PCR. In particular, one MPD mouse showed remarkable proliferation of blast cells in the lung, which might represent an extramedullar blast crisis. The results demonstrate that the expression of p210bcr/abl in hematopoietic progenitor cells in transgenic mice can contribute to two clinically distinct hematopoietic malignancies, CML and ALL, indicating that this transgenic system provides a novel transgenic model for human Ph1-positive leukemias.
 ...
PMID:Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias. 949 Jun 92

p210bcr/abl is detected in almost all chronic myelogenous leukemia (CML) patients and a significant number of acute lymphoblastic leukemia (ALL) cases. It is generated by a reciprocal chromosomal translocation, t(9;22) (q34;q11), and the enhanced kinase activity of the protein is believed to be implicated in the pathogenesis of the diseases. To examine its oncogenicity in vivo and to create an animal model for BCR/ABL-positive leukemias, we generated transgenic mice expressing p210bcr/abl driven by the promoter of the mouse tec gene, a cytoplasmic tyrosine kinase preferentially expressed in early hematopoietic progenitors. While the founder mice showed excessive proliferation of lymphoblasts shortly after birth and were diagnosed as ALL, the transgenic progeny reproducibly exhibited marked granulocyte hyperplasia with thrombocytosis after a long latent period, which closely resembles the clinical course of human CML. In addition, to investigate whether loss of p53 would play a role in the transition from chronic phase to blast crisis of CML, we crossmated p210bcr/abl transgenic (BCR/ABLtg/-) mice with p53 heterozygous (p53+/-) mice and generated p210bcr/abl transgenic, p53 heterozygous (BCR/ABLtg/- p53+/-) mice, in which a somatic alteration in the residual p53 allele directly abrogates p53 function. The BCR/ABLtg/- p53+/- mice exhibited rapid proliferation of blast cells and died in a short period compared with their wild-type (BCR/ABL-/- p53+/+), p53 heterozygous (BCR/ABL-/- p53+/-), and p210bcr/abl transgenic (BCR/ABLtg/- p53+/+) littermates. Interestingly, the normal p53 allele was frequently and preferentially lost in the tumor tissues, providing in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210bcr/abl-expressing hematopoietic cells. Our transgenic mice will be a useful model for investigating oncogenic properties of p210bcr/abl in vivo and will provide insights into the molecular mechanism(s) underlying the progression from chronic phase to blast crisis of CML.
 ...
PMID:Model mice for BCR/ABL-positive leukemias. 1135 87