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Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder. Cancer Cell 2009 Aug 04;16(2):137-48

Date

08/04/2009

Pubmed ID

19647224

Pubmed Central ID

PMC2763369

DOI

10.1016/j.ccr.2009.06.007

Scopus ID

2-s2.0-67651166902 (requires institutional sign-in at Scopus site)   61 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/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.

Author List

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

Author

Alice Boshoven MD Assistant Professor in the Family Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

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
RUNX1 Translocation Partner 1 Protein
Spleen