AML 细胞利用 TNF 驱动的 JNK 信号作为关键的 NF-κB 独立生存信号,Blood

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AML 细胞利用 TNF 驱动的 JNK 信号作为关键的 NF-κB 独立生存信号
Blood ( IF 21.0 ) Pub Date : 2013-11-15 , DOI: 10.1182/blood.v122.21.2890.2890
Andrew Volk ₁ , Jing Li ₂ , Junping Xin ₃ , Dewen You ₄ , Jun Zhang ₂ , Peter Breslin ₅ , Zejuan Li ₆ , Wei Wei ₄ , Rachel Schmidt ₃ , Xinyu Li ₂ , Zhou Zhang ₂ , Paul C Kuo ₇ , Sucha Nand ₈ , Jianke Zhang ₉ , Jianjun Chen ₆ , Jiwang Zhang ₄

Affiliation

与正常造血干细胞/祖细胞 (HSPC) 相比，从急性髓性白血病 (AML) 患者中分离的白血病干细胞 (LSC) 对体外培养中 NF-κB 抑制诱导的细胞死亡高度敏感。这表明阻断 NF-κB 可能是治疗 AML 的有效策略。然而，单独的 NF-κB 抑制剂治疗无法在体内清除 AML 肿瘤。我们认为这很可能是由于生态位微环境中的元素刺激了 AML 细胞中可以克服 NF-κB 抑制的补偿性存活/增殖信号。我们利用多方面的 AML 模型，其中包括由 MLL-AF9 转导的造血细胞、几种已建立的人类 AML 细胞系和从患者身上分离的原发性 AML 肿瘤创建的鼠系统。我们观察到 AML M3、4 和 5 名患者外周血中肿瘤坏死因子-α (TNF) 水平升高。我们的研究表明，这种 TNF 是由 AML 细胞直接产生的，并且 AML 细胞利用 TNF 来刺激 JNK 作为与白血病细胞中 NF-κB 平行的存活信号和 HSPC 中的死亡信号。在健康的 HSPC 中，外源性 TNF 的刺激会诱导 RIP1/3 介导的坏死性凋亡和半胱天冬酶介导的细胞凋亡，导致细胞死亡和正常造血功能的丧失。JNK 信号的失活可以部分挽救 HSPC 中 TNF 介导的功能丧失。此外，阻断 HSPC 中的 NF-κB 会使它们对 TNF 介导的细胞死亡敏感，这也可以通过 JNK 信号传导的失活来部分预防。这些数据表明 JNK 在 HSPC 中充当 TNF 介导的死亡信号。在反洗钱中，我们发现 TNF 信号通过同时刺激 NF-κB 和 JNK 信号，促进白血病细胞的体外生长并增强 AML 肿瘤的体内发育。我们确定白血病细胞中 TNF 介导的 JNK 信号导致关键存活信号的传播。这些细胞通过限制 JNK 活性持续时间以及上调 AP1 家族转录因子 c-Jun 的表达，将 TNF-JNK 刺激从死亡信号转化为生存信号。因此，白血病细胞中的 TNF-JNK 信号不会驱动细胞凋亡，而是驱动 c-Jun 活性和随后抗凋亡基因 c-Flip 和 Mcl-1 的产生。我们发现 TNF-JNK-AP1 信号轴的任何部分的失活都可以抑制体外白血病细胞的生长并延迟体内白血病的发生。我们还表明，阻断 TNF-JNK-AP1 信号轴的任何部分都会使表达 TNF 的白血病细胞（包括 LSC）对 NF-κB 抑制剂治疗敏感，同时保护 HSPC 免受此类治疗。总之，我们的研究表明，NF-κB 抑制在体内清除 AML 肿瘤的能力不足是由于 TNF 介导的 JNK-AP1 信号轴激活可以补偿 LSC 中的 NF-κB 信号抑制。我们发现许多类型的 AML 产生 TNF，这种 TNF 以自分泌方式通过 NF-κB 和 JNK-AP1 的平行激活促进 LSC 存活和自我更新，以及以旁分泌方式抑制正常造血. 所以，我们建议同时抑制 TNF-JNK-AP1 和 NF-κB 信号可能为外周血 TNF 升高的 AML 患者提供更彻底的治疗。披露：无相关利益冲突需要申报。

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AML Cells Utilize TNF-Driven JNK Signaling As a Critical NF-κB-Independent Survival Signal

Leukemic Stem Cells (LSCs) isolated from Acute Myeloid Leukemia (AML) patients are highly sensitive to NF-κB inhibition-induced cell death in in vitro culture when compared to normal hematopoietic stem/progenitor cells (HSPCs). This suggests blocking NF-κB could be an effective strategy for treating AML. However, NF-κB inhibitor treatment alone is unable to clear AML tumors in vivo . We propose this is most likely due to elements within the niche microenvironment stimulating compensatory survival/proliferation signals in AML cells that can overcome NF-κB inhibition. We utilize a multi-faceted AML model that includes a murine system created by MLL-AF9 transduced hematopoietic cells, several established human AML cell lines, and primary AML tumors isolated from patients. We observed elevated Tumor Necrosis Factor-α (TNF) levels in the peripheral blood of AML M3, 4, and 5 patients. Our studies suggest this TNF is produced directly by the AML cells, and that AML cells utilize TNF to stimulate JNK as a survival signal parallel to NF-κB in leukemic cells and a death signal in HSPCs. In healthy HSPCs, stimulation with exogenous TNF induces RIP1/3-mediated necroptosis and caspase-mediated apoptosis, resulting in cell death and loss of normal hematopoietic function. Inactivation of JNK signaling can partially rescue TNF-mediated loss of function in HSPCs. Additionally, blocking NF-κB in HSPCs sensitizes them to TNF-mediated cell death, which can also be partially prevented by inactivation of JNK signaling. These data suggest that JNK acts as a TNF-mediated death signal in HSPCs. In AML, we found TNF signaling promotes the in vitro growth of leukemic cells as well as enhancing the in vivo development of AML tumors by stimulation of both NF-κB and JNK signaling in parallel. We determined that TNF-mediated JNK signaling in leukemic cells results in the propagation of a critical survival signal. These cells convert TNF-JNK stimulation from a death to survival signal by limiting JNK activity duration as well as upregulating the expression of the AP1 family transcription factor c-Jun. Therefore, TNF-JNK signaling in leukemic cells does not drive apoptotic cell death, but instead drives c-Jun activity and the subsequent production of the anti-apoptotic genes c-Flip and Mcl-1. We found inactivation of any part of the TNF-JNK-AP1 signaling axis can repress the growth of leukemic cells in vitro and delay leukemogenesis in vivo . We also show that blocking any portion of the TNF-JNK-AP1 signaling axis sensitizes TNF-expressing leukemic cells, including LSCs, to NF-κB inhibitor treatment while at the same time protecting HSPCs from such treatment. In conclusion, our studies suggest that the inadequate ability of NF-κB inhibition to clear AML tumors in vivo is due to the TNF-mediated activation of the JNK-AP1 signaling axis that can compensate for NF-κB signal repression in LSCs. We found that many types of AMLs produce TNF, and this TNF acts both in an autocrine fashion to promote LSC survival and self-renewal through parallel activation of NF-κB and JNK-AP1, as well as in a paracrine fashion to repress normal hematopoiesis. Therefore, we propose that inhibition of both TNF-JNK-AP1 and NF-κB signals may provide a more thorough treatment for AML patients with elevated peripheral blood TNF. Disclosures: No relevant conflicts of interest to declare.

更新日期：2013-11-15

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