Brandts Christian H, Sargin Bülent, Rode Miriam, Biermann Christoph, Lindtner Beate, Schwäble Joachim, Buerger Horst, Müller-Tidow Carsten, Choudhary Chunaram, McMahon Martin, Berdel Wolfgang E, Serve Hubert
Department of Medicine, Hematology and Oncology, University of Münster, Germany.
Cancer Res. 2005 Nov 1;65(21):9643-50. doi: 10.1158/0008-5472.CAN-05-0422.
Up to 30% of patients with acute myeloid leukemia (AML) harbor internal tandem duplications (ITD) within the FLT3 gene, encoding a receptor tyrosine kinase. These mutations induce constitutive tyrosine kinase activity in the absence of the natural Flt3 ligand and confer growth factor independence, increased proliferation, and survival to myeloid precursor cells. The signaling pathways and downstream nuclear targets mediating leukemic transformation are only partly identified. Here, we show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a. Restored Foxo3a activity reversed Flt3-ITD-mediated growth properties and dominant-negative Akt prevented Flt3-ITD-mediated cytokine independence. Conditional Akt activation targeted to the cell membrane induced cytokine-independent survival, cell cycle progression, and proliferation. Importantly, Akt activation was sufficient to cause in vitro transformation of 32D myeloid progenitor cells and in vivo promoted the development of a leukemia-like myeloid disease. Akt phosphorylation was found in myeloid blasts of 86% of AML patients, suggesting an important role in leukemogenesis. In summary, Akt is necessary for increased survival, proliferation, and leukemic transformation by Flt3-ITD, possibly by inactivation of Foxo transcription factors. These findings indicate that Akt and Foxo transcription factors are attractive targets for therapeutic intervention in AML.
高达30%的急性髓系白血病（AML）患者在编码受体酪氨酸激酶的FLT3基因内存在内部串联重复（ITD）。这些突变在缺乏天然Flt3配体的情况下诱导组成型酪氨酸激酶活性，并赋予髓系前体细胞生长因子非依赖性、增殖增加和存活能力。介导白血病转化的信号通路和下游核靶点仅部分得到确定。在此，我们表明Flt3-ITD的存在组成型激活Akt（蛋白激酶B），这是磷脂酰肌醇3激酶途径中的一种关键丝氨酸-苏氨酸激酶。Akt的组成型激活使转录因子Foxo3a磷酸化并抑制其活性。恢复的Foxo3a活性逆转了Flt3-ITD介导的生长特性，而显性负性Akt阻止了Flt3-ITD介导的细胞因子非依赖性。靶向细胞膜的条件性Akt激活诱导细胞因子非依赖性存活、细胞周期进展和增殖。重要的是，Akt激活足以导致32D髓系祖细胞的体外转化，并在体内促进白血病样髓系疾病的发展。在86%的AML患者的髓系母细胞中发现了Akt磷酸化，提示其在白血病发生中起重要作用。总之，Akt对于Flt3-ITD增加存活、增殖和白血病转化是必需的，可能是通过使Foxo转录因子失活实现的。这些发现表明Akt和Foxo转录因子是AML治疗干预的有吸引力的靶点。
