Targeting Cathepsin-G to Overcome Leukemic Stem Cell Persistence in Chronic Myeloid

Chronic myeloid leukemia (CML) stem and progenitor cells (LSPCs) are not eliminated by tyrosine kinase inhibitors, resulting in disease relapse or progression. Transcriptomic profiling identified Cathepsin G ( CTSG ), a serine protease, as one of the top significantly upregulated targets in primary CML CD34 + cells compared to CD34 + cells from healthy donors (Log2 FC, p-value). Further, molecular inhibition of CTSG reduced the self-renewal capacity and diminished disease burden in vivo in a CDX mouse model, highlighting CTSG as a promising therapeutic target in CML. Pharmacological inhibition of CTSG demonstrated a dose-dependent decrease in CTSG expression and colony-forming capacity only in CML CD34 + cells. This study offers comprehensive insights into the gene expression landscape of CML LSPCs, highlighting the functional significance of CTSG in disease progression. Targeting CTSG could be a novel therapeutic strategy for CML treatment by disrupting the leukemogenic potential and improving therapeutic efficacy.