NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies with TP53 inactivation

Monosomy 7 (-7) and deletions of chromosome arm 7q (del(7q)) are prevalent high-risk cytogenetic abnormalities that often co-occur with del(17p) (harboring <i>TP53</i>). To identify novel targeted therapies based on specific vulnerabilities in high-risk myeloid malignancies, we investigated druggable, chromosome 7-encoded essential genes that are monoallelically deleted in the context of -7/del(7q), that is, collateral lethal genes. By mining genome-wide CRISPR-Cas9 screen data sets, we identified nicotinamide phosphoribosyltransferase (<i>NAMPT</i>) on 7q22.3 as a specific susceptibility in 81.5% of -7/del(7q) malignancies. Human acute myeloid leukemia (AML) cell lines with partial loss of <i>NAMPT</i> and primary samples from patients with -7 AML demonstrated heightened sensitivity to the NAMPT inhibitor KPT-9274 compared to control samples. Notably, NAMPT inhibitors were equally effective in <i>NAMPT</i>-deficient samples with <i>TP53</i> loss. Furthermore, combining NAMPT and poly (ADP-ribose) polymerase (PARP) inhibitors, which augment DNA damage, resulted in synergistic therapeutic effects in <i>NAMPT</i>-deficient AML cells. These findings indicate that <i>NAMPT</i> heterozygosity is a therapeutic vulnerability in high-risk myeloid malignancies with -7/del(7q) and recommend <i>NAMPT</i> levels as a biomarker for NAMPT inhibitor sensitivity. This study also establishes a data-driven framework for identifying collateral lethal genes in cancers with recurrent chromosomal deletions.