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This study identifies NAMPT as a critical therapeutic target in TP53 mutant mantle cell lymphoma (MCL), where its inhibition induces synthetic lethality by disrupting the DNA damage response. Unlike in wild-type cells, this mechanism sensitizes TP53 mutant MCL to alkylating chemotherapy and DDR-targeting therapies while maintaining a favorable safety profile.

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Abstract

Abstract Patients with TP53 mutant mantle cell lymphoma (MCL) face poor chemotherapy response and early progression, requiring novel therapies. Nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting nicotinamide adenine dinucleotide salvage enzyme overexpressed in MCL cell lines and patient tissues, emerges as a therapeutic target. The NAMPT inhibitor KPT-9274 reduced viability and induced apoptosis in MCL cells irrespective of TP53 status. Mechanistic studies reveal a striking dichotomy: in TP53 mutant cells, NAMPT inhibition triggers synthetic lethality through catastrophic DNA damage response (DDR) pathway disruption, whereas in TP53 wild-type cells, it selectively suppresses B-cell receptor (BCR) signaling and immune checkpoint activation. This biological divergence translates to clinically actionable synergies: TP53 mutant cells exhibit marked sensitization to alkylating agents and DDR-targeting therapies, whereas TP53 wild-type models show potential for overcoming BTK inhibitor resistance. In vivo studies confirm that NAMPT-based combinations achieve profound tumor regression in TP53 mutant xenografts without exacerbating toxicity. Our findings establish NAMPT as a dual-context therapeutic node, providing a precision medicine framework to circumvent chemoresistance in high-risk MCL. These results advocate for the clinical evaluation of TP53 status–guided NAMPT inhibitor combinations to address this unmet oncologic challenge.

Key findings

  • NAMPT is overexpressed in both MCL cell lines and patient tissues regardless of TP53 status.
  • Inhibition of NAMPT triggers catastrophic DNA damage response pathway disruption specifically in TP53 mutant cells, leading to synthetic lethality.
  • Combination therapy with NAMPT inhibitors significantly enhances the efficacy of alkylating agents in TP53 mutant MCL xenografts without increasing toxicity.

Keywords

Cancer researchDNA damageNicotinamide phosphoribosyltransferaseMantle cell lymphomaMutantApoptosis

Identifiers

DOI
10.1182/bloodadvances.2025016765
Journal
Blood Advances
Year
2026