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

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

Authors

  • Oravecz-Wilson KI
  • Philips ST
  • Yilmaz OH
  • Ames HM
  • Li L
  • Crawford BD
  • Gauvin AM
  • Lucas PC
  • Sitwala K
  • Downing JR
  • Morrison SJ
  • Ross TS

Journal

Cancer cell

Publication Data

August 4, 2009

Associated Grants

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

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
  • Leukemia, Myelomonocytic, Chronic
  • Mice
  • Mice, Transgenic
  • Myeloproliferative Disorders
  • Oncogene Proteins, Fusion
  • Piperazines
  • Pyrimidines
  • Spleen