Department of Pathology, Case Western Reserve University, Cleveland, OH.
Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) Biostatistics Center, Dana-Farber Cancer Institute, Boston, MA.
Blood Adv. 2018 Nov 13;2(21):2890-2903. doi: 10.1182/bloodadvances.2018016006.
Acute myeloid leukemia (AML) is a devastating disease with poor patient survival. As targetable mutations in AML are rare, novel oncogenic mechanisms are needed to define new therapeutic targets. We identified AML cells that exhibit an aberrant pool of nuclear glycogen synthase kinase 3β (GSK3β). This nuclear fraction drives AML growth and drug resistance. Nuclear, but not cytoplasmic, GSK3β enhances AML colony formation and AML growth in mouse models. Nuclear GSK3β drives AML partially by promoting nuclear localization of the NF-κB subunit, p65. Finally, nuclear GSK3β localization has clinical significance as it strongly correlates to worse patient survival (n = 86; hazard ratio = 2.2; < .01) and mediates drug resistance in cell and animal models. Nuclear localization of GSK3β may define a novel oncogenic mechanism in AML and represent a new therapeutic target.
急性髓细胞白血病（AML）是一种具有较差患者生存的毁灭性疾病。由于 AML 中可靶向的突变很少，因此需要新的致癌机制来定义新的治疗靶点。我们鉴定出 AML 细胞中存在异常核糖原合酶激酶 3β（GSK3β）池。该核部分驱动 AML 的生长和耐药性。核而非细胞质 GSK3β增强 AML 集落形成和 AML 在小鼠模型中的生长。核 GSK3β 通过促进 NF-κB 亚基 p65 的核定位来驱动 AML 的发生。最后，核 GSK3β 定位具有临床意义，因为它与更差的患者生存（n=86；风险比=2.2；<0.01）强烈相关，并在细胞和动物模型中介导耐药性。GSK3β 的核定位可能在 AML 中定义了一种新的致癌机制，并代表了一个新的治疗靶点。
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