Oravecz-Wilson Katherine I, Philips Steven T, Yilmaz Omer H, Ames Heather M, Li Lina, Crawford Brendan D, Gauvin Alice M, Lucas Peter C, Sitwala Kajal, Downing James R, Morrison Sean J, Ross Theodora S
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cancer Cell. 2009 Aug 4;16(2):137-48. doi: 10.1016/j.ccr.2009.06.007.
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 imatinib dramatically decreased disease burden, LICs persisted, demonstrating imatinib refractoriness of LICs.
尽管酪氨酸激酶抑制剂伊马替尼对慢性粒细胞白血病（CML）患者有显著疗效，但这种疗法很少能治愈CML患者，这可能是由于白血病起始细胞（LICs）对伊马替尼耐药。由于人CML-LICs在NOD-SCID小鼠中的植入效果不佳以及逆转录病毒转导小鼠模型中癌基因的非生理性表达，关于这一点的证据有限。为应对这些挑战，我们构建了携带两个人类癌基因条件性敲入等位基因的小鼠：HIP1/PDGFβR（H/P）和AML1-ETO（A/E）。与逆转录病毒转导不同，单独生理性表达H/P或A/E未能诱发疾病，但同时表达H/P和A/E会导致完全显性的骨髓增殖性疾病迅速发作，表明这两个等位基因之间存在协同作用。尽管伊马替尼显著降低了疾病负担，但LICs依然存在，证明了LICs对伊马替尼耐药。
