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/PDGFβR (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.
Original language | English (US) |
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Pages (from-to) | 137-148 |
Number of pages | 12 |
Journal | Cancer Cell |
Volume | 16 |
Issue number | 2 |
DOIs | |
State | Published - Aug 4 2009 |
Keywords
- CELLCYCLE
- STEMCELL
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research