Ibrutinib increases miR-181a/b in leukemic cells from patients with chronic lymphocytic leukemia Open Access

• Higher miR-181a/b levels in leukemic cells are linked to reduced white blood counts in CLL patients treated with ibrutinib

• Ibrutinib influences miR-181a/b expression via c-Fos involvement in CLL cells

Ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia (CLL), induces a high overall response rate with low toxicity. However, long-term follow-up reveals clinical relapse in several patients. Understanding the molecular mechanisms of this drug could help identify pathways of resistance. In this study, using a cohort of 60 longitudinal samples from 12 patients, we demonstrate that increased expression of miR-181a and miR-181b is associated with a reduction in white blood cell count in CLL patients treated with ibrutinib. The drug induces an upregulation of these pro-apoptotic miRNAs at the transcriptional level, which becomes evident as cells die. Furthermore, we report that ibrutinib elicits a reduction in c-Fos protein levels after 72 hours of treatment, a transcription factor that we demonstrated to be implicated in the regulatory control of miR-181a and miR-181b, thereby establishing a regulatory feedback loop linked to cell death. These findings provide further insight into how ibrutinib affects leukemic cells in CLL patients and offer a basis for investigating potential resistance mechanisms.