Persistence of Leukemia-Initiating Cells in a Conditional Knockin Model of an Imatinib-Responsive Myeloproliferative Disorder

Katherine I. Oravecz-Wilson, Steven T. Philips, Ömer H. Yilmaz, Heather M. Ames, Lina Li, Brendan D. Crawford, Alice M. Gauvin, Peter C. Lucas, Kajal Sitwala, James R. Downing, Sean J. Morrison, Theodora S. Ross

Research output: Contribution to journalArticle

54 Scopus citations

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 languageEnglish (US)
Pages (from-to)137-148
Number of pages12
JournalCancer Cell
Volume16
Issue number2
DOIs
StatePublished - Aug 4 2009

Keywords

  • CELLCYCLE
  • STEMCELL

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Oravecz-Wilson, K. I., Philips, S. T., Yilmaz, Ö. H., Ames, H. M., Li, L., Crawford, B. D., Gauvin, A. M., Lucas, P. C., Sitwala, K., Downing, J. R., Morrison, S. J., & Ross, T. S. (2009). Persistence of Leukemia-Initiating Cells in a Conditional Knockin Model of an Imatinib-Responsive Myeloproliferative Disorder. Cancer Cell, 16(2), 137-148. https://doi.org/10.1016/j.ccr.2009.06.007