Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes suggérant que, chez les patients traités pour une leucémie myéloïde chronique, la résistance aux inhibiteurs de tyrosine kinase est due à une instabilité génomique apparue dans des cellules souches réfractaires très primitives
Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in BCR-ABL1 mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or additional chromosomal aberrations leading to disease relapse and/or malignant progression. TKI-naive and TKI-treated leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage. To determine the role of TKI-refractory LSCs in genomic instability we employed a murine model of CML-CP where ROS-induced oxidative DNA damage were elevated in LSCs, including quiescent LSCs, but not in LPCs. ROS-induced oxidative DNA damage in LSCs caused clinically relevant genomic instability in CML-CP –like mice, such as TKI-resistant BCR-ABL1 mutations (E255K, T315I, H396P), deletions in Ikzf1 and Trp53, and additions in Zfp423 and Idh1. Despite inhibition of BCR-ABL1 kinase, imatinib did not downregulate ROS and oxidative DNA damage in TKI-refractory LSCs to the levels detected in normal cells, and CML-CP –like mice treated with imatinib continued to accumulate clinically relevant genetic aberrations. Inhibition of class I p21-activated protein kinases (PAKs) by IPA3 downregulated ROS in TKI-naïve and TKI-treated LSCs. Altogether, we postulate that genomic instability may originate in the most primitive TKI-refractory LSCs in TKI-naïve and TKI-treated patients.
Blood 2013