Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of imatinib on myeloproliferative disease in transgenic (Tg) mice expressing the P230 BCR/ABL transcript is unknown. To investigate this issue, we administered imatinib (30 mg/kg per day) orally to P230 BCR/ABL-expressing Tg mice for 30 days. Following imatinib administration, the enlarged spleen was significantly reduced to within the normal size range. Infiltrating megakaryocytes in the long-axis section of the spleen were also significantly reduced. However, the cellularity of the bone marrow was not affected. Fluorescence-activated cell-sorting analysis revealed that infiltrating mature granulocytes in the spleen were reduced in number. The numbers of infiltrating CD34, CD117, CD61, and CD11b populations were also reduced in immature populations of the spleen. Real-time quantitative polymerase chain reaction analysis of messenger RNA revealed a dramatic reduction in the p230 BCR/ABL transcript for CD34, CD117, CD61, and CD11b populations in both bone marrow cells and spleen cells. Western blotting and immunoprecipitation analysis also revealed a marked reduction in P230 BCR/ABL protein expression in both bone marrow cells and spleen cells. Thus, imatinib administration had the intriguing effect of replacing clones with high expression of p230 BCR/ABL complementary DNA with clones with very low expression. These data show that imatinib may still be capable of eliminating and eradicating clones with high p230 BCR/ABL expression and healing the disease phenotype in Tg mice. Pluripotent clones with very low p230 BCR/ABL expression still survive as immature CD34, CD117, CD61, and CD11b populations.
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PMID:Oral administration of imatinib to P230 BCR/ABL-expressing transgenic mice changes clones with high BCR/ABL complementary DNA expression into those with low expression. 1711 62

Our previous study showed that besides mRNAs and microRNAs, there are DNA fragments within extracellular vesicles (EVs). The BCR/ABL hybrid gene, involved in the pathogenesis of chronic myeloid leukemia (CML), could be transferred from K562 EVs to neutrophils and decrease their phagocytic activity in vitro. Our present study provides evidence that BCR/ABL DNAs transferred from EVs have pathophysiological significance in vivo. Two months after injection of K562 EVs into the tail vein of Sprague-Dawley (SD) rats, they showed some characteristics of CML, e.g., feeble, febrile, and thin, with splenomegaly and neutrophilia but with reduced neutrophil phagocytic activity. These findings were also observed in immunodeficient NOD/SCID mice treated with K562 EVs; BCR/ABL mRNA and protein were found in their neutrophils. The administration of actinomycin D, an inhibitor of de novo mRNA synthesis, prevented the abnormalities caused by K562 EVs in NOD/SCID mice related to CML, including neutrophilia and bone marrow hyperplasia. As a specific inhibitor of tyrosine kinases, imatinib blocked the activity of tyrosine kinases and the expression of phospho-Crkl, induced by the de novo BCR/ABL protein caused by K562 EVs bearing BCR/ABL DNA. Our current study shows the pathophysiological significance of transferred tumor gene from EVs in vivo, which may represent an important mechanism for tumorigenesis, tumor progression, and metastasis.
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PMID:Transferred BCR/ABL DNA from K562 extracellular vesicles causes chronic myeloid leukemia in immunodeficient mice. 2513 86