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

Cancer cell | Aug 4, 2009

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.

Pubmed ID: 19647224 RIS Download

Mesh terms: Animals | Antineoplastic Agents | Benzamides | Core Binding Factor Alpha 2 Subunit | DNA-Binding Proteins | Disease Models, Animal | Drug Resistance, Neoplasm | Gene Knock-In Techniques | Genotype | Hematopoietic Stem Cells | Humans | Imatinib Mesylate | Leukemia, Myelomonocytic, Chronic | Mice | Mice, Transgenic | Myeloproliferative Disorders | Oncogene Proteins, Fusion | Piperazines | Pyrimidines | Spleen

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA082363-04
  • Agency: NCI NIH HHS, Id: R01 CA098730
  • Agency: NCI NIH HHS, Id: R01 CA098730-04S1
  • Agency: NCI NIH HHS, Id: R01 CA082363-01A1
  • Agency: NCI NIH HHS, Id: R01 CA082363
  • Agency: NCI NIH HHS, Id: R01 CA82363-03
  • Agency: NCI NIH HHS, Id: T32 CA009676
  • Agency: NCI NIH HHS, Id: R01 CA082363-02
  • Agency: Howard Hughes Medical Institute, Id: R01 CA082363-05
  • Agency: NCI NIH HHS, Id: R01 CA098730-05A1
  • Agency: NCI NIH HHS, Id: R01 CA098730-01
  • Agency: NCI NIH HHS, Id: CA009676
  • Agency: NCI NIH HHS, Id: R01 CA082363-03
  • Agency: NCI NIH HHS, Id:

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