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Cancer Cell. 2009 Aug 4;16(2):137-48. doi: 10.1016/j.ccr.2009.06.007.

Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder.

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  • 1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Abstract

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.

PMID:
19647224
[PubMed - indexed for MEDLINE]
PMCID:
PMC2763369
Free PMC Article

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