Monosomy 7/del(7q) cause sensitivity to inhibitors of nicotinamide phosphoribosyltransferase in acute myeloid leukemia

• Published in: Blood advances 2024-04, Vol.8 (7), p.1621-1633
• Main Authors: Eldfors, Samuli, Saad, Joseph, Ikonen, Nemo, Malani, Disha, Vähä-Koskela, Markus, Gjertsen, Bjørn T., Kontro, Mika, Porkka, Kimmo, Heckman, Caroline A.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 7; Humans; Leukemia, Myeloid, Acute - genetics; Myeloid Neoplasia; Nicotinamide Phosphoribosyltransferase
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2023010435

•Monosomy 7 and del(7q) result in a 1-copy deletion of the NAMPT gene at 7q22.3.•NAMPT haploinsufficiency causes a vulnerability to the inhibition of NAMPT. [Display omitted] Monosomy 7 and del(7q) (-7/-7q) are frequent chromosomal abnormalities detected in up to 10% of patients with acute myeloid leukemia (AML). Despite unfavorable treatment outcomes, no approved targeted therapies exist for patients with -7/-7q. Therefore, we aimed to identify novel vulnerabilities. Through an analysis of data from ex vivo drug screens of 114 primary AML samples, we discovered that -7/-7q AML cells are highly sensitive to the inhibition of nicotinamide phosphoribosyltransferase (NAMPT). NAMPT is the rate-limiting enzyme in the nicotinamide adenine dinucleotide salvage pathway. Mechanistically, the NAMPT gene is located at 7q22.3, and deletion of 1 copy due to -7/-7q results in NAMPT haploinsufficiency, leading to reduced expression and a therapeutically targetable vulnerability to the inhibition of NAMPT. Our results show that in -7/-7q AML, differentiated CD34+CD38+ myeloblasts are more sensitive to the inhibition of NAMPT than less differentiated CD34+CD38– myeloblasts. Furthermore, the combination of the BCL2 inhibitor venetoclax and the NAMPT inhibitor KPT-9274 resulted in the death of significantly more leukemic blasts in AML samples with -7/-7q than the NAMPT inhibitor alone. In conclusion, our findings demonstrate that AML with -7/-7q is 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).