Monosomy 7/del(7q) cause sensitivity to inhibitors of nicotinamide phosphoribosyltransferase in acute myeloid leukemia.
Blood Adv
; 8(7): 1621-1633, 2024 Apr 09.
Article
en En
| MEDLINE
| ID: mdl-38197948
ABSTRACT
ABSTRACT 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).
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1
Base de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
/
Antineoplásicos
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
Blood Adv
Año:
2024
Tipo del documento:
Article