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Haematological cancer

Repositioned to attack CML cells

Nature Reviews Clinical Oncology volume 12, page 624 (2015)Cite this article

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BCR–ABL1 tyrosine kinase inhibitors (TKIs) enable effective long-term management of chronic myeloid leukaemia (CML). However, complete molecular responses (CMRs)—when the CML BCR–ABL1 molecular signature is undetectable—are rare; in patients without a CMR, relapse is common when TKIs are stopped. Now, Prost et al. have shown that antidiabetic PPARγ agonists can invoke sustained CMRs in patients without a CMR to the TKI imatinib.

“Pioglitazone and other PPARγ agonists can progressively erode the pool of quiescent CML stem cells, which are responsible for residual disease during continuous TKI therapy and relapse when TKIs are interrupted,” explains Philippe Leboulch, who co-led the study. Analyses in CML cells showed that pioglitazone synergizes with imatinib: imatinib effectively depletes proliferating CML cells only, while pioglitazone causes resistant CML stem cells to exit quiescence, sensitizing them to the TKI. Mechanistically, PPARγ agonism downregulated STAT5 and its targets HIF2α and CITED2 (a regulator of haematopoietic-stem-cell quiescence), which were overexpressed in CML stem cells.

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References

  1. Prost, S. et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists. Nature 10.1038/nature15248

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  1. David Killock
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Killock, D. Repositioned to attack CML cells. Nat Rev Clin Oncol 12, 624 (2015). https://doi.org/10.1038/nrclinonc.2015.166

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