Bone Marrow CD34+/lin- Cells of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) After 12 Months of Nilotinib Treatment Exhibit a Different Gene Expression Signature Compared to the Diagnosis and the Corresponding Cells from Healthy Subjects.

Background: Chronic-Phase Chronic Myeloid Leukemia (C-PCML) is defined by the presence of the fusion gene, which encodes a tyrosine kinase protein that drives the uncontrolled proliferation and survival of leukemic stem cells (LSCs). Nilotinib, a tyrosine kinase inhibitor, targets the activity of BCR-ABL1 by reducing aberrant signaling pathways, which drive the regeneration of LSCs. Despite nilotinib's action, a population of resilient LSCs persist in the bone marrow (BM) and can indeed drive relapse and progression in CML patients.

Methods: Our study investigated the gene expression profiling (GEP) of BM CD34+/lin- cells from 79 CP-CML patients at diagnosis, compared to the BM CD34+/lin- cells from the same patients after 12 months of nilotinib treatment and to the normal counterpart cells from 10 donors (CTRLs).

Results: GEP analyses identified 3012 significantly differentially expressed genes across these comparisons. Among these, we focused on certain key genes associated with eight crucial KEGG pathways: CML, cell cycle, JAK-STAT, PI3K-Akt, MAPK, Ras, NF-kB, and ABC transporters. Within these pathways, we observed the up-regulation of several genes at diagnosis compared to both 12 months of nilotinib treatment and the CTRLs.

Conclusions: We observed that certain transcriptome features present at diagnosis persisted after 12 months of nilotinib treatment, compared to CTRLs. This suggests that nilotinib may exert selective pressure, potentially supporting the survival and self-renewal of LSCs. Future insights into these pathways could help identify therapeutic targets to improve outcomes in CML.