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

• NAMPT is a therapeutic vulnerability that can be pharmacologically targeted in high-risk TP53 deficient -7/del(7q) myeloid malignancies

• CRISPR-Cas9 screening and genomics can be combined to identify collateral lethal genes in cancers characterized by recurrent chromosomal arm-level deletions.

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 TP53). To identify novel targeted therapies based on specific vulnerabilities in high-risk myeloid malignancies, we investigated druggable, chromosome 7-encoded essential genes that are mono-allelically deleted in the context of -7/del(7q), i.e., collateral lethal genes. By mining genome-wide CRISPR-Cas9 screen datasets, we identified nicotinamide phosphoribosyltransferase (NAMPT) on 7q22.3 as a specific susceptibility in 81.5% of -7/del(7q) malignancies. Both human acute myeloid leukemia (AML) cell lines with NAMPT partial loss and primary -7 AML patient samples demonstrated heightened sensitivity to the NAMPT inhibitor KPT-9274 compared to control samples. Notably, NAMPT inhibitors were equally effective in NAMPT-deficient samples with TP53 loss. Furthermore, combining NAMPT and PARP inhibitors, which augment DNA damage, resulted in synergistic therapeutic effects in NAMPT-deficient AML cells. These findings indicate that NAMPT heterozygosity is a therapeutic vulnerability in high-risk myeloid malignancies with -7/del(7q) and recommend NAMPT 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.