UC San Diego

Chronic myeloid leukemia (CML) results from the BCR-ABL1 fusion protein that skews hematopoietic stem cell differentiation toward the myeloid lineage, creating an aberrantly self-renewing progenitor population that gives rise to leukemia stem cells (LSCs). While effective at reducing symptoms, current treatments target BCR-ABL1 with tyrosine kinase inhibitors (TKIs) but fail to eradicate the niche-resident LSCs responsible for patient relapse and CML disease progression to its terminal stage, blast crisis (BC). Previous studies indicated that the extracellular matrix (ECM) could play a significant role in promoting LSC survival by demonstrating that niche- resident LSCs exhibit resistance to pharmacological inhibition by adopting stem cell-like behaviors such as quiescence, self-renewal and preferential expression of pro-survival BCL2 family isoforms. Analysis of LSCs through RT-PCR ECM array and RNA-seq identified a significant increase in BC versus chronic phase (CP) CML expression of connective tissue growth factor (CTGF), an ECM protein that has been linked to poor prognoses in multiple cancers. Lentivirally-enforced CTGF expression in the BC CML cell line, K562, increased pro-survival BCL2 family isoform expression and conferred chemoresistance to TKI treatment. Increased CTGF expression in CP CML LSCs was also associated with increased pro-survival BCL2 family isoform expression, and a trend for increased self- renewal. Cumulatively, these results indicate that CTGF could play a crucial role in CML LSC maintenance, enhancing survival, chemoresistance and, potentially, self -renewal. Therefore, delineating the role of CTGF in CML LSC maintenance could elucidate the process of BC transformation, resulting in biomarkers that predict patient outcome or novel targets for therapeutic intervention