Résumé
Heterogeneity within the CML patient population is evidenced by variable response dynamics and tolerability between patients treated with tyrosine kinase inhibitors (TKIs). Clinical risk scores have utility however do not inform upon the biology underpinning differential response. OCT1 activity has been established as a predictor of imatinib response but is not predictive for second generation TKIs nilotinib or dasatinib.
In CML, microRNAs (miRNAs) have been implicated in BCR-ABL mediated signalling pathways and alter rapidly after TKI treatment. Indeed, we have previously established that miR-142-3p decreases within 14 days of TKI initiation and correlates with the SOKAL score.
We performed miRNA profiling on 75 newly diagnosed, clinical trial CML patients (56% male, 44% female, median age 51 years) with greater than 24 months follow-up. RNA was extracted from peripheral blood mononuclear cells. The expression of 800 mature miRNA was analysed using the nCounter Human v2 miRNA Expression Assay (NanoString Technologies). In addition, IC50 values for imatinib and nilotinib were determined on all samples as previously described.
The miRNA expression levels obtained on this platform showed a wide dynamic range and substantial interpatient variation. This included miRNA previously reported in CML in vitro and patient studies: interquartile ranges were 52414 to 121632 for miR-142-3p, 3120 to 15599 for miR-451a, 2658 to 12023 for miR-150, 828 to 1461 for miR-181a-5p. In addition, we were able to identify miRNAs that were associated with nilotinib IC50 and imatinib IC50.
The current study highlights the variability evident at the miRNA level between newly diagnosed CML patients. It provides a rationale to further examine the role of miRNA in CML pathogenesis, TKI response and define patient heterogeneity from diagnosis.
White:Novartis: Research Funding; BMS: Research Funding, Speakers Bureau; Ariad: Research Funding; CSL: Research Funding. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.