FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia
FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia
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DOI：
10.1007/s00277-014-2085-1
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发表时间：
2014-09-01
影响因子：
3.5
通讯作者：
Teshima, Takanori
中科院分区：
文献类型：
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作者：
Iwasaki, Junko;Kondo, Takeshi;Teshima, Takanori
FIP 1样1（FIP 1 L1）与两种致白血病融合基因相关：FIP 1 L1-视黄酸受体α（RARA）和FIP 1 L1-血小板衍生生长因子受体α（PDGFRA）。对一系列缺失突变体的分析表明，FIP 1 L1-RARA中的FIP 1基序在其同源二聚化和转录抑制活性中起着关键作用。然而，在FIP 1 L1-PDGFRA中，C-末端PDGFRA部分具有自身形成同源二聚体的能力，使得FIP 1 L1能够组成性激活该激酶。FIP 1 L1-PDGFRA的全长和C-末端PDGFRA部分均可转化IL-3依赖性造血细胞系BAF-B 03。此外，当FIP 1 L1-PDGFRA的全长或C-末端PDGFRA部分被引入这些细胞中时，它们在不存在IL-3的情况下生长。然而，具有FIP 1 L1-PDGFRA的C-末端PDGFRA部分的细胞是部分IL-3依赖性的，而具有全长FIP 1 L1-PDGFRA的细胞的生长变得完全不依赖于IL-3。总之，这些结果表明，FIP 1 L1差异有助于不同类型的白血病的发病机制。
FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1-retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full-length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL-3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full-length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia.