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  • Original Article
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Toward a therapeutic reduction of imatinib refractory myeloproliferative neoplasm-initiating cells

Oncogene volume 33, pages 5379–5390 (2014)Cite this article

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Abstract

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.

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Abbreviations

A/E:

AML1/ETO

CBC:

complete blood count

CML:

chronic myelogenous leukemia

CMML:

chronic myelomonocytic leukemia

Cy/G:

cyclophosphamide/G-CSF

Cytarabine:

ara-C

GMP:

granulocyte/monocyte progenitor

H/P:

HIP1/PDGFβR

H/P;A/E:

genotype of Mx1-Cre;Hip1LSL-hp/+;Aml1LSL-AE/+

HSC:

hematopoietic stem cell

HSPC:

hematopoietic stem and progenitor cell

LIC:

leukemia initiating cell

LK:

lineage−c-Kit+ immunophenotype

LSK:

lineage−Sca-1+c-Kit+ immunophenotype

LS:

lineage-Sca-1+c-Kit+/− immunophenotype

LT-HSC:

long-term hematopoietic stem cell

MPN:

myeloproliferative neoplasm

MPP:

multipotent progenitor

pIpC:

polyinosinic-polycytidylic acid

ST-HSC:

short-term hematopoietic stem cell

TKI:

tyrosine kinase inhibitor

WBC:

white blood cell count.

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Acknowledgements

We thank Bob Rooney, Luke Peterson, Phil (Zhe) Guan, Ivan Maillard, Yipin Wu and Alice Gauvin for their intellectual input and technical assistance. This work was supported by the following grants: CBTG CA009676 (STP), R01 CA82363-03 (TSR) and R01 CA098730-01 (TSR), and a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research (TSR). TSR holds the Jeanne Ann Plitt Professorship in Breast Cancer Research and the H Ben and Isabelle T Decherd Chair in Internal Medicine at UT Southwestern Medical Center. TSR was supported as a Leukemia and Lymphoma Society Scholar during the time this work was completed.

Author Contributions

STP, ZLH, KIOW and SBF performed, designed, edited and interpreted the research. TSR designed and interpreted the research. TSR, STP and VEM wrote the paper.

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  1. S T Philips and Z L Hildenbrand: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX, USA

    S T Philips, Z L Hildenbrand, S B Foley, V E Mgbemena & T S Ross

  2. University of Michigan, Ann Arbor, MI, USA

    K I Oravecz-Wilson

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Correspondence to T S Ross.

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Philips, S., Hildenbrand, Z., Oravecz-Wilson, K. et al. Toward a therapeutic reduction of imatinib refractory myeloproliferative neoplasm-initiating cells. Oncogene 33, 5379–5390 (2014). https://doi.org/10.1038/onc.2013.484

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