NAMPT haploinsufficiency is a therapeutic vulnerability to NAMPT inhibition in -7/-7q MDS.

Chromosome 7 abnormalities -7 and -7q define a high-risk subset of myelodysplastic syndromes (MDS) with poor prognosis. The NAMPT gene, located at 7q22.3, encodes a rate limiting enzyme (nicotinamide phosphoribosyl transferase) in the NAD+ salvage pathway. Several inhibitors of NAMPT have been developed, but their activity in MDS has not been previously described. In this study, we investigated if MDS myeloblasts are susceptible to NAMPT inhibition. We show that primary bone marrow cells from patients with -7/-7q MDS exhibit strong and select sensitivity. Bulk viability assays and single cell, multiparametric flow cytometry confirmed enhanced NAMPT inhibitor sensitivity across leukemic cell populations, especially CD34 + CD38+ blasts from -7/-7q MDS samples compared to non -7/-7q MDS and healthy donor bone marrow cells. The NAMPT inhibitor KPT-9274 combined with BCL2 inhibitor venetoclax was particularly effective at targeting MDS blasts compared to NAMPT inhibition alone. MDS samples with -7/-7q also showed significantly lower NAMPT expression compared to the non -7/-7q samples, indicative of haploinsufficient gene expression profile. In conclusion, these findings support NAMPT haploinsufficiency as a vulnerability and as biomarker for NAMPT inhibitor activity in -7/-7q MDS.