Breitenbuecher Frank, Markova Boyka, Kasper Stefan, Carius Birgit, Stauder Torsten, Böhmer Frank D, Masson Kristina, Rönnstrand Lars, Huber Christoph, Kindler Thomas, Fischer Thomas
3rd Medical Department, Johannes Gutenberg-University, Mainz, Germany.
Blood. 2009 Apr 23;113(17):4063-73. doi: 10.1182/blood-2007-11-126664. Epub 2009 Jan 14.
Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the beta-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA interference technology, deregulated MCL-1 protein expression was shown to play a major role in conferring the resistance phenotype of 32D_ITD627E cells. Enhanced and sustained binding of the adaptor protein GRB-2 to the FLT3_ITD627E receptor is involved in MCL-1 up-regulation and is independent from TKI (PKC412)-induced inhibition of the receptor kinase. Thus, we describe a new mechanism of primary resistance to TKIs, which operates by reprogramming local and distant signal transduction events of the FLT3 tyrosine kinase. The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs.
目前，FMS样酪氨酸激酶3（FLT3）酪氨酸激酶抑制剂（TKIs）正成为克服携带FLT3内部串联重复（ITD）的急性髓性白血病（AML）患者预后不良的最有前景的药物治疗方法。然而，约30%的患者会出现初始耐药，且耐药的分子机制尚不清楚。在此，我们发现了AML中对FLT3 TKIs原发性耐药的一种新机制：一种携带非近膜ITD的FLT3受体非典型地整合到第一个激酶结构域的β-2折叠中（FLT3_ITD627E），可诱导抗凋亡髓系细胞白血病1蛋白（MCL-1）显著上调。使用RNA干扰技术表明，失调的MCL-1蛋白表达在赋予32D_ITD627E细胞耐药表型中起主要作用。衔接蛋白GRB-2与FLT3_ITD627E受体的增强和持续结合参与MCL-1上调，且独立于TKI（PKC412）诱导的受体激酶抑制。因此，我们描述了一种对TKIs原发性耐药的新机制，该机制通过重新编程FLT3酪氨酸激酶的局部和远距离信号转导事件起作用。所呈现的数据表明，FLT3的特定ITD可能与信号重连和对TKIs的不同反应性相关。
