UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Cell Death Dis. 2023 Sep 8;14(9):599. doi: 10.1038/s41419-023-06122-2.
Deletion of TRAF2 or TRAF3 in B cells prolongs their survival. However, it remains unknown whether deletion of such factors affects B cells' ability to tolerate DNA damage, which can be induced by chemotherapeutics and cause apoptosis. Genetic alterations of TRAF2 or TRAF3 are observed in subsets of human B-cell lymphomas and B cell-specific deletion of TRAF3 led to lymphoma development in aged mice. However, it remains unknown whether double deficiency of TRAF2 and TRAF3 accelerates B-cell lymphomagenesis. Here, we showed that B cell-specific TRAF2/3 double deficient (B-TRAF2/3-DKO) B cells were remarkably more resistant to DNA damage-induced apoptosis via upregulating cIAP2 and XIAP, which in turn attenuates caspase-3 activation. Mechanistically, resistance to DNA damage-induced apoptosis required NF-κB2, which effects by upregulating XIAP and cIAP2 transcription. B-TRAF2/3-DKO mice exhibited a shorter lifespan and succumbed to splenomegaly and lymphadenopathy. Unexpectedly, the incidence of B-cell lymphoma development in B-TRAF2/3-DKO mice was relatively rare (∼10%). Sequencing B cell receptor repertoire of diseased B cells revealed that TRAF2/3 deficiency caused abnormal oligoclonal or clonal expansion of B cells. While a fraction of mutant B cells (25-43%) from aged diseased mice harbored recurrent chromosomal translocations, primary B cells isolated from young B-TRAF2/3-DKO mice had no detectable chromosomal alterations, suggesting that TRAF2/3 deficiency per se does not cause evident genomic instability in B cells. Chemo-resistant TRAF3-deficient B-cell lymphomas were sensitized to chemotherapeutic drugs by blocking IAP activity using IAP antagonist. We conclude that double deficiency of TRAF2 and TRAF3 does not accelerate B-cell lymphomagenesis. Our studies provide insight into mechanisms regulating DNA damage-induced apoptosis and may help develop effective therapies targeting mutant B-cell lymphomas using IAP antagonist.
B 细胞中 TRAF2 或 TRAF3 的缺失会延长其存活时间。然而，目前尚不清楚这些因子的缺失是否会影响 B 细胞耐受化疗药物诱导的 DNA 损伤的能力，这种损伤可导致细胞凋亡。在人类 B 细胞淋巴瘤的亚群中观察到 TRAF2 或 TRAF3 的基因改变，并且 B 细胞特异性 TRAF3 的缺失会导致老年小鼠发生淋巴瘤。然而，目前尚不清楚 TRAF2 和 TRAF3 的双重缺失是否会加速 B 细胞淋巴瘤的发生。在这里，我们发现 B 细胞特异性 TRAF2/3 双重缺失（B-TRAF2/3-DKO）B 细胞对 DNA 损伤诱导的凋亡具有更强的抗性，这是通过上调 cIAP2 和 XIAP 实现的，从而减弱了 caspase-3 的激活。在机制上，对 DNA 损伤诱导的凋亡的抗性需要 NF-κB2，NF-κB2 通过上调 XIAP 和 cIAP2 的转录来发挥作用。B-TRAF2/3-DKO 小鼠的寿命更短，并死于脾肿大和淋巴结病。出乎意料的是，B-TRAF2/3-DKO 小鼠中 B 细胞淋巴瘤的发生率相对较低（约 10%）。对患病 B 细胞的 B 细胞受体库进行测序表明，TRAF2/3 的缺失导致 B 细胞异常的寡克隆或克隆性扩增。虽然来自老年患病小鼠的部分突变 B 细胞（25-43%）携带反复发生的染色体易位，但从小鼠中分离的年轻 B-TRAF2/3-DKO B 细胞没有检测到染色体改变，这表明 TRAF2/3 的缺失本身不会导致 B 细胞明显的基因组不稳定性。使用 IAP 拮抗剂阻断 IAP 活性可使化疗耐药的 TRAF3 缺失的 B 细胞淋巴瘤对化疗药物敏感。我们的结论是，TRAF2 和 TRAF3 的双重缺失不会加速 B 细胞淋巴瘤的发生。我们的研究为调节 DNA 损伤诱导的细胞凋亡的机制提供了深入的了解，并可能有助于使用 IAP 拮抗剂为靶向突变 B 细胞淋巴瘤开发有效的治疗方法。
