Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571.
The murine bone marrow retroviral transduction and transplantation model of chronic myelogenous leukemia (CML) imperfectly mimics human CML because the murine CML-like disease causes death of all animals from an overwhelming granulocytosis within 3 to 4 weeks. In this report, mice reconstituted with P210(BCR/ABL)-transduced bone marrow cells received posttransplantation therapy with either the tyrosine kinase inhibitor STI571 or placebo. Compared with the rapidly fatal leukemia of placebo-treated animals, 80% of the STI571-treated mice were alive on day 74, with marked improvement in peripheral white blood counts and splenomegaly. There was decreased tyrosine phosphorylation of STAT5, Shc, and Crk-L in leukemic cells from STI571-treated animals, consistent with STI571-mediated inhibition of the Bcr/Abl tyrosine kinase in vivo. In some STI571-treated animals Bcr/Abl messenger RNA and protein expression were markedly increased. In contrast to the polyclonal leukemia of placebo-treated mice, STI571-treated murine CML was generally oligoclonal, suggesting that STI571 eliminated or severely suppressed certain leukemic clones. None of the STI571-treated mice were cured of the CML-like myeloproliferative disorder, however, and STI571-treated murine CML was transplanted to secondary recipients with high efficiency. These results demonstrate the utility of this murine model of CML in the evaluation of novel therapeutic agents against Bcr/Abl-induced leukemias. This improved murine chronic-phase CML model may be a useful tool for the study of STI571 resistance, CML progression, and the anti-CML immune response.
Wolff
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NC
Division of Hematology/Oncology, Department of Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
Ilaria
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RL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D000068877:Imatinib Mesylate; D017874:Immediate-Early Proteins / Q000235:genetics; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D007958:Leukocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008894:Milk Proteins; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D050799:STAT5 Transcription Factor; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D050826:Suppressor of Cytokine Signaling Proteins; D015996:Survival Rate; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014161:Transduction, Genetic
D000970:Antineoplastic Agents; D001549:Benzamides; D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D017874:Immediate-Early Proteins; D008894:Milk Proteins; D010879:Piperazines; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators