Flt3 does not play a critical role in murine myeloid leukemias induced by MLL fusion genes.
Flt3 does not play a critical role in murine myeloid leukemias induced by MLL fusion genes.
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DOI：
10.1371/journal.pone.0072261
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lavau C
中科院分区：
文献类型：
--
作者：
Albouhair S;Morgado E;Lavau C
携带MLL易位的白血病在儿童和成人中很常见，并且对治疗反应很差。受体酪氨酸激酶FLT 3在这些白血病中高度表达。体外研究表明，小儿ML重排ALL细胞对FLT 3抑制剂敏感，临床试验正在进行中，以测量其治疗效果。我们试图确定Flt 3在MLL重排的白血病的发病机制中的作用，使用骨髓性白血病小鼠模型。将来自用MLL-ENL或MLL-CBP转导的Flt 3缺失小鼠的骨髓移植到宿主小鼠中，并将Flt 3 −/−白血病与其Flt 3野生型对应物进行比较。Flt 3缺乏不会延迟疾病发作，对白血病特征的影响很小。为了确定FLT 3抑制的抗白血病作用，我们研究了MLL-ENL白血病细胞对FLT 3抑制剂PKC 412的离体敏感性。如先前对于人ML重排白血病所报道的，具有较高Flt 3水平的鼠MLL-ENL白血病细胞对PKC 412的细胞毒性更敏感。有趣的是，Flt 3缺陷型白血病样品也显示出对PKC 412的一些敏感性。我们的研究结果表明，由MLL重排基因诱导的髓系白血病不依赖于Flt 3信号。他们还强调了体外细胞对Flt 3抑制的敏感性与体内Flt 3对MLL重排白血病发病机制缺乏贡献之间的差异。
Leukemias harboring MLL translocations are frequent in children and adults, and respond poorly to therapies. The receptor tyrosine kinase FLT3 is highly expressed in these leukemias. In vitro studies have shown that pediatric MLL-rearranged ALL cells are sensitive to FLT3 inhibitors and clinical trials are ongoing to measure their therapeutic efficacy. We sought to determine the contribution of Flt3 in the pathogenesis of MLL-rearranged leukemias using a myeloid leukemia mouse model. Bone marrow from Flt3 null mice transduced with MLL-ENL or MLL-CBP was transplanted into host mice and Flt3 −/− leukemias were compared to their Flt3 wild type counterparts. Flt3 deficiency did not delay disease onset and had minimal impact on leukemia characteristics. To determine the anti-leukemic effect of FLT3 inhibition we studied the sensitivity of MLL-ENL leukemia cells to the FLT3 inhibitor PKC412 ex vivo. As previously reported for human MLL-rearranged leukemias, murine MLL-ENL leukemia cells with higher Flt3 levels were more sensitive to the cytotoxicity of PKC412. Interestingly, Flt3 deficient leukemia samples also displayed some sensitivity to PKC412. Our findings demonstrate that myeloid leukemias induced by MLL-rearranged genes are not dependent upon Flt3 signaling. They also highlight the discrepancy between the sensitivity of cells to Flt3 inhibition in vitro and the lack of contribution of Flt3 to the pathogenesis of MLL-rearranged leukemias in vivo.
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影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
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20.3
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11.4
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