Cyclin-dependent kinase 2 (Cdk2) activity at the G1 to S boundary has a role in the resistance of Chronic Myeloid Leukemia (CML) haematopoietic progenitors to the tyrosine kinase inhibitor STI571 (Imatinib)

Unrestrained progression throughout the cell cycle, mostly resulting from abrogation of the G1/S checkpoint, has a key role in the pathogenesis and progression of CML. It permits, in fact, the illegitimate enlargement of clonal hematopoiesis over its normal counterpart and causes the genomic instability that drives further progression of CML towards the fully transformed phenotype of its terminal phase, the blast crisis. It is conditional upon the constitutive tyrosine kinase activity of the p210 protein of bcr-abl rearranged gene, the molecular marker of CML. Accordingly, the tyrosine kinase inhibitor STI571 (Imatinib), approved as the first-choice drug in the treatment of CML since 2001, significantly improved the prognosis of CML. More recently, the outcomes of large clinical trials uncovered the Achille heel of STI571, the drug resistance occurring at variable intervals from the beginning of therapy and likely arising from the selection of clonal myeloid progenitors bearing additional, drug-insensitive biomolecular traits. In our previous studies we proved that Cdk2 has a role in the early escape from STI571 of CML hematopoiesis (Mazzacurati et al, The Hematology Journal, 5, 168-177, 2004). Here, we confirmed that Cdk2 is constitutively activated in STI571-resistant clonal hematopoietic progenitors in spite of the drug pharmacological effects on its target, the p210 bcr-abl tyrosine kinase. Multiple pathways participate in sustaining Cdk2 enzymatic activity associated with resistance to STI571. They include: 1- the persistence of Cdc25A phosphatase (that activates Cdk2 by removing the inhibitory phosphorylation at Thr 14 and Tyr15), resulting, in turn, from the downmodulation of Chk2 serin-threonin kinase (that under adverse conditions addresses Cdc25A to the ubiquitin-dependent/proteasome mediated degradation) and of 14.3.3 chaperon protein (that binds Cdc25A and keeps it inactive within the cytoplasmatic compartment) as well as from the upmodulation of c-Myc (that transcriptionally regulates Cdc25A); 2- the down-modulation of Wee 1 (that provides the Cdk2 inhibitory phosphorylation at Tyr15). In conclusion, our results address to Cdk2 as an early molecular marker of responsiveness to STI571 of CML hematopoietic progenitors. Moreover and more importantly, they contribute to the identification of additional signals whose targeting, combined with the inhibition of p210 bcr-abl tyrosine kinase, may greatly help to improve the CML prognosis and circumvent the selection of drug-resistant clones