Explaining the in vitro and in vivo differences in leukemia therapy

Tom Lenaerts, Fausto Castagnetti, Arne Traulsen, Jorge M. Pacheco, Gianantonio Rosti, David M Dingli

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The majority of patients with chronic myeloid leukemia in early chronic phase (CML-ECP) who are treated with imatinib achieve a complete cytogenetic response with a significant reduction in the risk of progression to advanced phases. Recent studies show that therapy of CML-ECP with nilotinib leads to a faster and deeper response compared to imatinib. However, in vitro data indicates that there is no detectable difference in inhibition of signaling downstream of Bcr-Abl between the two agents and that neither drug induces apoptosis of CML CD34+ cells. We use a computational model of hematopoiesis and CML, combined with serial quantitative data of disease burden under imatinib and nilotinib therapy to explain this apparent disconnect between in vivo and in vitro responses. We show how a subtle difference in the differentiation rate of CML cells under therapy with either agent, with marginal impact onto the in vitro studies, translates into a significantly different reproductive fitness of treated cells in vivo, providing a sizeable difference, hence providing an explanation for the superior response observed with nilotinib.

Original languageEnglish (US)
Pages (from-to)1540-1544
Number of pages5
JournalCell Cycle
Volume10
Issue number10
DOIs
StatePublished - May 15 2011

Fingerprint

Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Genetic Fitness
Hematopoiesis
Risk Reduction Behavior
Cell- and Tissue-Based Therapy
Cytogenetics
Therapeutics
Apoptosis
Pharmaceutical Preparations
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Imatinib Mesylate
In Vitro Techniques
Inhibition (Psychology)

Keywords

  • Evolution
  • Hematopoiesis
  • Reproductive fitness
  • Selection
  • Self-renewal

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Lenaerts, T., Castagnetti, F., Traulsen, A., Pacheco, J. M., Rosti, G., & Dingli, D. M. (2011). Explaining the in vitro and in vivo differences in leukemia therapy. Cell Cycle, 10(10), 1540-1544. https://doi.org/10.4161/cc.10.10.15518

Explaining the in vitro and in vivo differences in leukemia therapy. / Lenaerts, Tom; Castagnetti, Fausto; Traulsen, Arne; Pacheco, Jorge M.; Rosti, Gianantonio; Dingli, David M.

In: Cell Cycle, Vol. 10, No. 10, 15.05.2011, p. 1540-1544.

Research output: Contribution to journalArticle

Lenaerts, T, Castagnetti, F, Traulsen, A, Pacheco, JM, Rosti, G & Dingli, DM 2011, 'Explaining the in vitro and in vivo differences in leukemia therapy', Cell Cycle, vol. 10, no. 10, pp. 1540-1544. https://doi.org/10.4161/cc.10.10.15518
Lenaerts T, Castagnetti F, Traulsen A, Pacheco JM, Rosti G, Dingli DM. Explaining the in vitro and in vivo differences in leukemia therapy. Cell Cycle. 2011 May 15;10(10):1540-1544. https://doi.org/10.4161/cc.10.10.15518
Lenaerts, Tom ; Castagnetti, Fausto ; Traulsen, Arne ; Pacheco, Jorge M. ; Rosti, Gianantonio ; Dingli, David M. / Explaining the in vitro and in vivo differences in leukemia therapy. In: Cell Cycle. 2011 ; Vol. 10, No. 10. pp. 1540-1544.
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