Effects of plerixafor in combination with BCR-ABL kinase inhibition in a murine model of CML

Anupriya Agarwal, Angela G. Fleischman, Curtis L. Petersen, Ryan MacKenzie, Samuel Luty, Marc Loriaux, Brian Druker, Randall (Randy) Woltjer, Michael W. Deininger

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Sequestration in the bone marrow niche may allow leukemic stem cells to evade exposure to drugs. Because the CXCR4/SDF-1 axis is an important mechanism of leukemic stem cell interaction with marrow stroma, we tested whether plerixafor, an antagonist of CXCR4, may dislodge chronic myeloid leukemia (CML) cells from the niche, sensitizing them to tyrosine kinase inhibitors. We initially treated mice with retrovirally induced CML-like disease with imatinib plus plerixafor. Plerixafor mobilized CXCR4+ cells, but no difference was observed in leukemia burden, possibly reflecting insufficient disease control by imatinib. In a second series of experiments, we tested the combination of plerixafor with dasatinib in the same as well as an attenuated CML model. Despite much improved leukemia control, plerixafor failed to reduce leukemia burden over dasatinib alone. In addition, mice receiving plerixafor had an increased incidence of neurologic symptoms in association with CNS infiltration by BCR-ABL-expressing cells. We conclude that plerixafor is ineffective in reducing leukemia burden in this model but promotes CNS infiltration. Beneficial effects of combining tyrosine kinase inhibitors with plerixafor may be observed in a situation of minimal residual disease, but caution is warranted when disease control is incomplete.

Original languageEnglish (US)
Pages (from-to)2658-2668
Number of pages11
JournalBlood
Volume120
Issue number13
DOIs
StatePublished - Sep 27 2012

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Leukemia
Disease control
Stem cells
Infiltration
Protein-Tyrosine Kinases
Stem Cells
Bone Marrow
JM 3100
Residual Neoplasm
Myeloid Cells
Neurologic Manifestations
Cell Communication
Bone
Incidence
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Agarwal, A., Fleischman, A. G., Petersen, C. L., MacKenzie, R., Luty, S., Loriaux, M., ... Deininger, M. W. (2012). Effects of plerixafor in combination with BCR-ABL kinase inhibition in a murine model of CML. Blood, 120(13), 2658-2668. https://doi.org/10.1182/blood-2011-05-355396

Effects of plerixafor in combination with BCR-ABL kinase inhibition in a murine model of CML. / Agarwal, Anupriya; Fleischman, Angela G.; Petersen, Curtis L.; MacKenzie, Ryan; Luty, Samuel; Loriaux, Marc; Druker, Brian; Woltjer, Randall (Randy); Deininger, Michael W.

In: Blood, Vol. 120, No. 13, 27.09.2012, p. 2658-2668.

Research output: Contribution to journalArticle

Agarwal, Anupriya ; Fleischman, Angela G. ; Petersen, Curtis L. ; MacKenzie, Ryan ; Luty, Samuel ; Loriaux, Marc ; Druker, Brian ; Woltjer, Randall (Randy) ; Deininger, Michael W. / Effects of plerixafor in combination with BCR-ABL kinase inhibition in a murine model of CML. In: Blood. 2012 ; Vol. 120, No. 13. pp. 2658-2668.
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