A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657.
A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657.
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DOI：
10.1182/blood-2002-06-1800
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发表时间：
2003-04
期刊：
影响因子：
20.3
通讯作者：
J. Sohal;Vernon T. Phan;Philip V. Chan;Elizabeth M. Davis;Bhumi Patel;Louise M. Kelly;T. Abrams;A. O'Farrell;D. G. Gilliland;M. L. Le Beau;Scott C. Kogan
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文献类型：
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作者：
J. Sohal;Vernon T. Phan;Philip V. Chan;Elizabeth M. Davis;Bhumi Patel;Louise M. Kelly;T. Abrams;A. O'Farrell;D. G. Gilliland;M. L. Le Beau;Scott C. Kogan
PML-RAR α融合蛋白是急性早幼粒细胞白血病（APL）发病机制的核心。该蛋白在转基因小鼠中的表达可引发具有人类APL特征的髓系白血病，但潜伏期较长（MRP8 PML-RARA小鼠为8.5个月）。因此，额外的变化有助于白血病转化。FLT3受体酪氨酸激酶的激活突变在人类急性髓性白血病中很常见，在人类APL中也很常见。为了评估FLT3激活突变如何促进APL发病机制和影响治疗，我们使用逆转录病毒转导将FLT3激活等位基因引入对照和MRP8 PML-RARA转基因骨髓。激活的FLT3与PML-RAR α联合诱导白血病的时间为62 ~ 299天（中位潜伏期为105天）。与MRP8 PML-RARA小鼠自发产生的白血病相反，活化的FLT3/PML-RAR α白血病的特征是白细胞增多，类似于FLT3突变的人类APL。细胞遗传学分析显示克隆核型异常，这可能有助于发病或进展。SU11657是一种靶向FLT3的选择性口服多靶点酪氨酸激酶抑制剂，与全反式维甲酸联合可快速引起白血病的消退。我们的研究结果表明，预先存在t的细胞获得FLT3突变（15;17）是APL发展的常见途径。我们的研究结果还表明，FLT3突变的APL患者可能受益于全反式维甲酸加FLT3抑制剂的联合治疗。
The PML-RAR alpha fusion protein is central to the pathogenesis of acute promyelocytic leukemia (APL). Expression of this protein in transgenic mice initiates myeloid leukemias with features of human APL, but only after a long latency (8.5 months in MRP8 PML-RARA mice). Thus, additional changes contribute to leukemic transformation. Activating mutations of the FLT3 receptor tyrosine kinase are common in human acute myeloid leukemias and are frequent in human APL. To assess how activating mutations of FLT3 contribute to APL pathogenesis and impact therapy, we used retroviral transduction to introduce an activated allele of FLT3 into control and MRP8 PML-RARA transgenic bone marrow. Activated FLT3 cooperated with PML-RAR alpha to induce leukemias in 62 to 299 days (median latency, 105 days). In contrast to the leukemias that arose spontaneously in MRP8 PML-RARA mice, the activated FLT3/PML-RAR alpha leukemias were characterized by leukocytosis, similar to human APL with FLT3 mutations. Cytogenetic analysis revealed clonal karyotypic abnormalities, which may contribute to pathogenesis or progression. SU11657, a selective, oral, multitargeted tyrosine kinase inhibitor that targets FLT3, cooperated with all-trans retinoic acid to rapidly cause regression of leukemia. Our results suggest that the acquisition of FLT3 mutations by cells with a pre-existing t(15;17) is a frequent pathway to the development of APL. Our findings also indicate that APL patients with FLT3 mutations may benefit from combination therapy with all-trans retinoic acid plus an FLT3 inhibitor.