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

ABSTRACT

Monosomy 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, the NAMPT gene is located at 7q22.1, and deletion of one copy due to -7/-7q results in NAMPT haploinsufficiency. 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).

Competing Interest Statement

Conflict-of-interest disclosure: BTG has served as a consultant for BerGenBio and Pfizer Inc.; holds stock options in privately-held companies Alden Cancer Therapy and KinN Therapeutics; has provided consultancy services to Novartis. MK is an advisor for Novartis, Faron Pharmaceuticals, Bristol-Myers Squibb, Pfizer, and AbbVie; has received consultancy fees, research funding, and speaker's bureau involvement from AbbVie, as well as consultancy fees from Astellas Pharma. KP has been awarded honoraria from Pfizer, Novartis, Incyte, Bristol-Myers Squibb, Astellas, and AbbVie; has received research funding from Celgene/Bristol-Myers Squibb, Incyte, Pfizer, and Novartis. CAH has received research funding from Oncopeptides, IMI2 projects HARMONY and HARMONY PLUS, WntResearch, Orion, Kronos Bio, Novartis, Celgene, Zentalis Pharmaceuticals, and Amgen; has been awarded honoraria from Amgen. The remaining author declares no competing financial interests.

Funding Statement

This work was supported by the University of Helsinki, Cancer Foundation Finland, the Academy of Finland (grants 334781, 1320185) (C.A.H.), (grant 334273), the Sigrid Juselius Foundation and the Magnus Ehrnrooth Foundation (S.E.).

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Ethics committee/IRB of the Helsinki University Hospital gave ethical approval for this work in compliance with the Declaration of Helsinki.

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Footnotes

Presented in oral abstract form at the 65th annual meeting of the American Society of Hematology, New Orleans, LA, 15 November 2022.

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