Monosomy 7/del(7q) Cause Sensitivity to Inhibitors of Nicotinamide Phosphoribosyltransferase in Acute Myeloid Leukemia

Abstract

ABSTRACTMonosomy 7 and del(7q) (-7/-7q) are frequent chromosomal abnormalities detected in up to 10% of acute myeloid leukemia (AML) patients. Despite unfavorable treatment outcomes, no approved targeted therapies exist for patients with -7/-7q. Therefore, we aimed to identify novel therapeutic vulnerabilities in AML with -7/-7q. Through an analysis of data from ex vivo drug screens in 270 primary AML samples, we discovered that -7/-7q AML cells are highly sensitive to the inhibition of nicotinamide phosphoribosyltransferase (NAMPT). NAMPT is a rate-limiting enzyme in the NAD+ salvage pathway. Mechanistically, theNAMPTgene is located at 7q22.1, and deletion of one copy due to -7/-7q results inNAMPThaploinsufficiency. This leads to reduced gene expression and a therapeutically targetable vulnerability to the inhibition of NAMPT. Our results show that in -7/-7q AML, differentiated CD34+CD38+ progenitor cells are the most sensitive to the inhibition of NAMPT. In addition, we found that the combination of BCL2 inhibitor venetoclax and a NAMPT inhibitor efficiently eradicated undifferentiated AML blasts with -7/-7q. In conclusion, our findings demonstrate that AML samples with -7/-7q are highly sensitive to NAMPT inhibition, suggesting that NAMPT inhibitors have the potential to be an effective targeted therapy for patients with monosomy 7 or del(7q).KEY POINTSMonosomy 7 and del(7q) result in a one-copy deletion of the NAMPT gene at 7q22.1NAMPT haploinsufficiency causes a vulnerability to the inhibition of NAMPT