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.
Oravecz-Wilson
Katherine I
KI
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Philips
Steven T
ST
Yilmaz
Omer H
OH
Ames
Heather M
HM
Li
Lina
L
Crawford
Brendan D
BD
Gauvin
Alice M
AM
Lucas
Peter C
PC
Sitwala
Kajal
K
Downing
James R
JR
Morrison
Sean J
SJ
Ross
Theodora S
TS
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D055879:Gene Knock-In Techniques; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D000075142:RUNX1 Translocation Partner 1 Protein; D013154:Spleen / Q000378:metabolism / Q000473:pathology
C107844:AML1-ETO fusion protein, human; D000970:Antineoplastic Agents; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000075142:RUNX1 Translocation Partner 1 Protein; D000068877:Imatinib Mesylate