Abstract
Identifying precise targets of individual cancers remains challenging. Chronic lymphocytic leukemia (CLL) represents the most common adult hematologic malignancy, and trisomy 12 (tri12) represents a quarter of CLL patients. We report that tri12 human pluripotent stem cells (hPSCs) allow for the identification of gene networks and targets specific to tri12, which are controlled by comparative normal PSCs. Identified targets are upregulated in tri12 leukemic cells from a cohort of 159 patients with monoclonal B cell lymphocytosis and CLL. tri12 signaling patterns significantly influence progression-free survival. Actionable targets are identified using high-content drug testing and functionally validated in an additional 44 CLL patient samples. Using xenograft models, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor is potent and selective against human tri12 CLL versus healthy patient-derived xenografts. Our study uses hPSCs to uncover targets from genetic aberrations and apply them to cancer. These findings provide immediate translational potential as biomarkers and targets for therapeutic intervention.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common adult hematologic malignancy and leads to acquired immune dysfunction and related complications in most patients (Parikh, 2018; Stewart and Wild, 2014)
Characterization of human tri12 PSC as a genetic model for tri12 CLL disease Spontaneous acquisition of cytogenetic aberrations upon prolonged culture of human pluripotent stem cells (hPSCs) has been associated with detrimental consequences to properties of normal PSCs (Ben-David et al, 2014; Draper et al, 2004; Herszfeld et al, 2006; International Stem Cell Initiative et al, 2011; Werbowetski-Ogilvie et al, 2009)
Gene set enrichment analysis (GSEA) showed enrichment of cancer-related pathways in tri12 PSCs compared with normal PSCs (Figure 1C), which is similar to a previous report (BenDavid et al, 2014)
Summary
Chronic lymphocytic leukemia (CLL) is the most common adult hematologic malignancy and leads to acquired immune dysfunction and related complications in most patients (Parikh, 2018; Stewart and Wild, 2014). Cytogenetic analysis of CLL patient samples shows a relatively small number of recurrent cytogenetic aberrations that have been incorporated into standard of care using fluorescence in situ hybridization (FISH) (Dohner et al, 2000; Parikh et al, 2016). All FISH-based cytogenetic abnormalities are observed in IGHV-mutated (IGHV-M) and IGHV-unmutated (IGHV-U) cases, with the latter experiencing a worse prognosis (Hu et al, 2019; Morabito et al, 2013)
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