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 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 kinases and it regulates a variety of protein kinases involved in cell survival, motility and proliferation. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD), which 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 orthotopic xenograft murine models using patient-derived BALL cells. Although KPT-9274 affected both PAK4 signaling pathways and NAD+ dependent pathways, B-ALL cell growth inhibition mediated by KPT-9274 was largely abolished by nicotinic acid supplementation, indicating that the inhibitory effect of KPT- 9274 on B-ALL cell growth was mainly exerted by NAD+ depletion through blockade of NAMPT enzyme activity. Moreover, we found that B-ALL cells were especially vulnerable to NAD+ depletion, and the susceptibility to treatment with KPT-9274 was related to the reduced NAD+ reserve in B-ALL cells. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL. cDNA microarray based expression analyses was performed on B-cell ALL cell lines REH, RS4;11 and SEM under control and treated conditions. All experiments were carried out in duplicates.