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.
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.
Inami
Mitsuharu
M
Division of Hematology, Department of Third Internal Medicine, Nippon Medical School, Tokyo, Japan.
Inokuchi
Koiti
K
Yamaguchi
Hiroki
H
Nakayama
Kazutaka
K
Watanabe
Ayako
A
Uchida
Naoya
N
Tanosaki
Sakae
S
Dan
Kazuo
K
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides; D002465:Cell Movement; D002470:Cell Survival; D002999:Clone Cells; D018076:DNA, Complementary; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D016130:Immunophenotyping; D008533:Megakaryocytes / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000473:pathology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013163:Splenomegaly / Q000473:pathology; D016896:Treatment Outcome
D001549:Benzamides; D018076:DNA, Complementary; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl