FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression
FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression
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DOI：
10.1182/blood-2004-06-2498
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发表时间：
2005-01-15
期刊：
影响因子：
20.3
通讯作者：
Small, D
中科院分区：
文献类型：
--
作者：
Brown, P;Levis, M;Small, D
FMS 样酪氨酸激酶 3 (FLT3) 在 B 前体儿童急性淋巴细胞白血病 (ALL) 中几乎普遍表达。具有 MLL 基因重排的 ALL 病例和具有高超二倍体（> 50 条染色体）的 ALL 病例表达最高水平的 FLT3，FLT3 激活突变发生在 18% 的 MLL 重排病例和 28% 的超二倍体 ALL 病例中。我们确定了 CEP-701（一种有效的选择性 FLT3 抑制剂）在 8 个 ALL 细胞系和 39 个诊断时从患有各种 ALL 亚型的婴儿和儿童获得的骨髓样本中的抗白血病活性。与低表达水平的样本（13%，In = 13；P = .0003）相比，CEP-701 在表达高水平 FLT3 的样本中（74%，n = 23）诱导了明显的细胞凋亡反应。在具有 MLL 基因重排（82%，In = 11；P = .0005）、高超二倍体（100%，In 5；P = .0007）和/或 FLT3 突变（100%，n = 4；P = .0021）的样品中，对 FLT3 抑制的敏感性特别高。通过免疫印迹检查的 7 个敏感样品中的 7 个表明组成型磷酸化的 FLT3 受到 CEP701 的有效抑制，而 6 个耐药样品中的 0 个表达组成型磷酸化的 FLT3。我们得出结论，FLT3 抑制剂 CEP-701 有效抑制 FLT3 驱动的白血病细胞存活。 CEP-701 作为治疗儿童 ALL 的新型分子靶向药物进行临床测试是有必要的。 (C) 2005 年，美国血液学会。
FMS-like tyrosine kinase 3 (FLT3) is almost universally expressed in B-precursor childhood acute lymphoblastic leukemia (ALL). Cases of ALL with MLL gene rearrangements and those with high hyperdiploidy (> 50 chromosomes) express the highest levels of FLT3, and activating mutations of FLT3 occur in 18% of MLL-rearranged and 28% of hyperdiploid ALL cases. We determined the antileukemic activity of CEP-701, a potent and selective FLT3 inhibitor, in 8 ALL cell lines and 39 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL. CEP-701 induced pronounced apoptotic responses in a higher percentage of samples that expressed high levels of FLT3 (74%, n = 23) compared with samples with low levels of expression (13%, In = 13; P = .0003). Sensitivity to FLT3 inhibition was particularly high in samples with MLL gene rearrangements (82%, In = 11; P = .0005), high hyperdiploidy (100%, In 5; P = .0007), and/or FLT3 mutations (100%, n = 4; P = .0021). Seven of 7 sensitive samples examined by immunoblotting demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP701, whereas 0 of 6 resistant samples expressed constitutively phosphorylated FLT3. We conclude that the FLT3 inhibitor CEP-701 effectively suppresses FLT3-driven leukemic cell survival. Clinical testing of CEP-701 as a novel molecularly targeted agent for the treatment of childhood ALL is warranted. (C) 2005 by The American Society of Hematology.