Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Blood. 2024 Jun 6;143(23):2414-2424. doi: 10.1182/blood.2023022804.
Hyperactivation of the NF-κB cascade propagates oncogenic signaling and proinflammation, which together augments disease burden in myeloproliferative neoplasms (MPNs). Here, we systematically ablate NF-κB signaling effectors to identify core dependencies using a series of primary samples and syngeneic and patient-derived xenograft (PDX) mouse models. Conditional knockout of Rela attenuated Jak2V617F- and MPLW515L-driven onset of polycythemia vera and myelofibrosis disease hallmarks, respectively. In PDXs, RELA knockout diminished leukemic engraftment and bone marrow fibrosis while extending survival. Knockout of upstream effector Myd88 also alleviated disease burden; conversely, perturbation of negative regulator miR-146a microRNA induced earlier lethality and exacerbated disease. Perturbation of NF-κB effectors further skewed the abundance and distribution of hematopoietic multipotent progenitors. Finally, pharmacological targeting of interleukin-1 receptor-associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in nondiseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.
NF-κB 级联的过度激活会促进致癌信号和炎症前状态，这两者共同增加了骨髓增殖性肿瘤（MPN）的疾病负担。在这里，我们使用一系列原代样本和同基因及患者来源异种移植（PDX）小鼠模型，系统性地敲除 NF-κB 信号效应器，以确定核心依赖性。Rela 的条件性敲除分别减弱了 Jak2V617F 和 MPLW515L 驱动的真性红细胞增多症和骨髓纤维化疾病特征的发生。在 PDX 中，REL 敲除减少了白血病的植入和骨髓纤维化，同时延长了生存期。上游效应物 Myd88 的敲除也减轻了疾病负担；相反，负调控 miR-146a microRNA 的扰动导致更早的死亡和疾病恶化。NF-κB 效应器的扰动进一步改变了造血多能祖细胞的丰度和分布。最后，用抑制剂 CA-4948 靶向白细胞介素-1 受体相关激酶 4（IRAK4）进行药理学靶向治疗，特异性地抑制了 MPN 的疾病负担和炎症细胞因子，而在未患病模型中没有诱导毒性。这些发现突出了 MPN 中的脆弱性，这些脆弱性可以通过新兴的治疗方法加以利用。
