biostudies-literatureOravecz-Wilson KIHoward Hughes Medical InstituteNCI NIH HHS137-48https://www.ebi.ac.uk/biostudies/studies/S-EPMC2763369biostudies-literatureUnknown16(2)Despite remarkable responses to the tyrosine kinase inhibitor imatinib, CML patients are rarely cured by this therapy perhaps due to imatinib refractoriness of leukemia-initiating cells (LICs). Evidence for this is limited because of poor engraftment of human CML-LICs in NOD-SCID mice and nonphysiologic expression of oncogenes in retroviral transduction mouse models. To address these challenges, we generated mice bearing conditional knockin alleles of two human oncogenes: HIP1/PDGFbetaR (H/P) and AML1-ETO (A/E). Unlike retroviral transduction, physiologic expression of H/P or A/E individually failed to induce disease, but coexpression of both H/P and A/E led to rapid onset of a fully penetrant, myeloproliferative disorder, indicating cooperativity between these two alleles. Although imatinCancer cellPersistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder.PMC2763369R01 CA098730-01T32 CA009676R01 CA082363-05R01 CA082363-04R01 CA082363CA009676R01 CA082363-03R01 CA098730-04S1R01 CA082363-02R01 CA082363-01A1R01 CA82363-03R01 CA098730-05A1R01 CA098730Sitwala KRoss TSCrawford BDAmes HMGauvin AMMorrison SJPhilips STYilmaz OHDowning JRLucas PCLi LOravecz-Wilson KIfalsePersistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder.Despite remarkable responses to the tyrosine kinase inhibitor imatinib, CML patients are rarely cured by this therapy perhaps due to imatinib refractoriness of leukemia-initiating cells (LICs). Evidence for this is limited because of poor engraftment of human CML-LICs in NOD-SCID mice and nonphysiologic expression of oncogenes in retroviral transduction mouse models. To address these challenges, we generated mice bearing conditional knockin alleles of two human oncogenes: HIP1/PDGFbetaR (H/P) and AML1-ETO (A/E). Unlike retroviral transduction, physiologic expression of H/P or A/E individually failed to induce disease, but coexpression of both H/P and A/E led to rapid onset of a fully penetrant, myeloproliferative disorder, indicating cooperativity between these two alleles. Although imatin2009-01-01T00:00:00Z2009 Aug2025-06-01T12:36:21.115Z2019-03-27T00:25:58ZS-EPMC27633691964722410.1016/j.ccr.2009.06.007