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  • Original Article
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Acute lymphoblastic leukemia

Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia


Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD+ depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD+ reserve. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL.

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We thank Professor Dario Campana (National University of Singapore) for kindly providing OP-1 cells. We thank Professor Chng Wee Joo, Associate Professor Motomi Osato (Cancer Science Institute of Singapore) and Associate Professor Allen Yeoh (National University of Singapore) for sharing materials and advice. We thank Associate Professor Takaomi Sanda, Dr Shojiro Kitajima (Cancer Science Institute of Singapore) and Dr Takahiro Kamiya (National University of Singapore) for helpful discussion. This research was supported by the National Research Foundation Singapore under its Singapore Translational Research (STaR) Investigator Award (NMRC/STaR/0007/2008 and NMRC/STaR/0021/2014), and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), the NMRC Centre Grant awarded to National University Cancer Institute of Singapore, the National Research Foundation Singapore, the Singapore Ministry of Education under its Research Centres of Excellence initiatives and the US National Institutes of Health Grant R01CA026038-35. This study was partially supported by a generous donation from the Melamed family, Reuben Yeroushalmi and Blanche and Steven Koegler.

Author contributions

ST designed the study, performed experiments, analyzed the data and wrote the manuscript. WC performed experiments and analyzed the data. VM and D-CL discussed the data and provided helpful suggestion. AM performed bioinformatics analysis. L-WD, Q-YS, MS, LX, YC, Y-YJ, SG and ML provided helpful suggestion. MM and EP provided PDX B-ALL cells and helpful advice for handling them. WS and EB provided KPT-9274 and its information. HPK supervised and designed the study, discussed the data and helped write the manuscript.

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Correspondence to S Takao.

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Competing interests

WS and EB are employees of Karyopharm Therapeutics. The other authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Takao, S., Chien, W., Madan, V. et al. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia 32, 616–625 (2018).

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