Toward a therapeutic reduction of imatinib refractory myeloproliferative neoplasm-initiating cells.
Myeloproliferative neoplasms (MPNs) such as chronic myelogenous (CML) and chronic myelomonocytic leukemias (CMML) are frequently induced by tyrosine kinase oncogenes. Although these MPNs are sensitive to tyrosine kinase inhibitors such as imatinib, patients often relapse upon withdrawal of therapy. We used a model of MPN, which is induced by co-expression of the oncoproteins HIP1/PDGFβR (H/P) and AML1/ETO from their endogenous loci, to examine the mechanisms of disease development and recurrence following imatinib withdrawal. Although the MPN displayed a full hematologic response to imatinib, 100% of the diseased mice relapsed upon drug withdrawal. MPN persistence was not due to imatinib resistance mutations in the H/P oncogene or massive gene expression changes. Within 1 week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (lineage(-)Sca-1(+)c-Kit(+) immunophenotype) normalized. Supplementation of imatinib with granulocyte colony-stimulating factor or arsenic trioxide reduced MPN-initiating cell frequencies and the combination of imatinib with arsenic trioxide cured a large fraction of mice with MPNs. In contrast, no mice in the imatinib-treated control cohorts were cured. These data suggest that treatment with a combination of arsenic trioxide and imatinib can eliminate refractory MPN-initiating cells and reduce disease relapse.
Division of Hematology/Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX, USA.
S T
ST
Philips
Division of Hematology/Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX, USA.
Z L
ZL
Hildenbrand
University of Michigan, Ann Arbor, MI, USA.
K I
KI
Oravecz-Wilson
Division of Hematology/Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX, USA.
S B
SB
Foley
Division of Hematology/Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX, USA.
V E
VE
Mgbemena
Division of Hematology/Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX, USA.
T S
TS
Ross
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010087:Oxides / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001152:Arsenicals; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C489536:Hip1 protein, mouse; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; C493726:Runx1 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D000077237:Arsenic Trioxide