Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease
Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease
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DOI：
10.1084/jem.20061444
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发表时间：
2006-10-30
影响因子：
15.3
通讯作者：
Pure, Ellen
中科院分区：
文献类型：
--
作者：
Middleton, Melissa Kristine;Zukas, Alicia Marie;Pure, Ellen
虽然Abl抑制剂通常是慢性粒细胞白血病（CML）初始阶段的成功疗法，但难治性病例突出了对新分子见解的需求。我们证明，在酶12/15-脂氧合酶（12/15-LO）的小鼠缺乏发展骨髓增生性疾病（MPD），进展为可移植性白血病。尽管与Abl的失调无关，但从慢性阶段12/15-LO缺陷（Alox 15）小鼠分离的细胞表现出磷脂酰肌醇3-激酶（PI 3-K）途径的活化增加，如Akt的磷酸化增强所示。此外，转录因子干扰素共有序列结合蛋白（ICSBP）被过度磷酸化，并显示减少的核积累，转化为癌蛋白Bcl-2的表达水平增加。ICSBP缺陷、Bcl-2水平过高以及与慢性Alox 15 MPD相关的白血病细胞存活时间延长均在PI 3-K抑制剂治疗后可逆。值得注意的是，Alox 15 MPD向白血病的演变与RNA水平上ICSBP的额外调节相关，突出了Alox 15模型在理解CML向危机转变方面的潜在有用性。最后，12/15-LO表达抑制人CML衍生细胞系的生长。这些数据确定12/15-LO作为MPD的一个重要抑制因子，通过其作为一个关键的上游效应在PI 3-K依赖性ICSBP磷酸化的调节作用。
Though Abl inhibitors are often successful therapies for the initial stages of chronic myelogenous leukemia (CML), refractory cases highlight the need for novel molecular insights. We demonstrate that mice deficient in the enzyme 12/15-lipoxygenase (12/15-LO) develop a myeloproliferative disorder (MPD) that progresses to transplantable leukemia. Although not associated with dysregulation of Abl, cells isolated from chronic stage 12/15-LO-deficient (Alox15) mice exhibit increased activation of the phosphatidylinositol 3-kinase (PI3-K) pathway, as indicated by enhanced phosphorylation of Akt. Furthermore, the transcription factor interferon consensus sequence binding protein (ICSBP) is hyperphosphorylated and displays decreased nuclear accumulation, translating into increased levels of expression of the oncoprotein Bcl-2. The ICSBP defect, exaggerated levels of Bcl-2, and prolonged leukemic cell survival associated with chronic stage Alox15 MPD are all reversible upon treatment with a PI3-K inhibitor. Remarkably, the evolution of Alox15 MPD to leukemia is associated with additional regulation of ICSBP on an RNA level, highlighting the potential usefulness of the Alox15 model for understanding the transition of CML to crisis. Finally, 12/15-LO expression suppresses the growth of a human CML-derived cell line. These data identify 12/15-LO as an important suppressor of MPD via its role as a critical upstream effector in the regulation of PI3-K-dependent ICSBP phosphorylation.