Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia.
Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia.
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DOI：
10.1016/j.exphem.2013.11.008
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发表时间：
2014-03
影响因子：
2.6
通讯作者：
Snoeck, Hans-Willem
中科院分区：
文献类型：
--
作者：
Kamezaki, Kenjiro;Luchsinger, Larry L.;Snoeck, Hans-Willem
Flt3基因是急性白血病中最常见的突变基因之一。然而，在许多血液系统恶性肿瘤中高度表达的wt Flt3在白血病发生中的作用尚不清楚。在通过逆转录病毒转导白血病融合蛋白建立的小鼠模型中，Flt3的缺失强烈地抑制了MLL-ENL，并在较小程度上抑制了p210BCR-ABL诱导的白血病发生，但在MLL-AF9或AML1-ETO9a模型中没有影响。Flt3在白血病干细胞(LSCs)水平发挥作用，在MLL-ENL中作为LSCs的一部分，但在MLL-AF9诱导的白血病中不表达，在体内表达Flt3，在该模型中LSCs上Flt3的表达与白血病的发生有关。此外，转导Flt3+后，MLL-enl诱导白血病的效率显著高于Flt3−，而MLL-AF9诱导的白血病诱导效率没有显著提高。然而，MLL-enl体外诱导骨髓细胞永生化不需要Flt3，也不影响MLL-enl LSCs的体外集落形成，提示体外模型不能反映MLL-enl白血病对Flt3的体内生物学要求。我们得出结论，wt Flt3在体内启动白血病中起作用，然而，这并不是普遍存在的。
FLT3 is one of the most frequently mutated genes in acute leukemias. However, the role in leukemogenesis of wt Flt3, which is highly expressed in many hematological malignancies, is unclear. We show here that in mouse models established by retroviral transduction of leukemic fusion proteins deletion of Flt3 strongly inhibits MLL-ENL and to lesser extent p210BCR-ABL-induced leukemogenesis, but has no effect in MLL-AF9 or AML1-ETO9a models. Flt3 acts at the level of leukemic stem cells (LSCs), as a fraction of LSCs in MLL-ENL, but not in MLL-AF9-induced leukemia, expressed Flt3 in vivo, and Flt3 expression on LSCs was associated with leukemia development in this model. Furthermore, efficiency of MLL-ENL, but not of MLL-AF9-induced leukemia induction was significantly enhanced after transduction of Flt3+ compared to Flt3− wt myeloid progenitors. However, Flt3 is not required for immortalization of bone marrow cells in vitro by MLL-ENL and does not affect colony-formation by MLL-ENL LSCs in vitro, suggesting that in vitro models do not reflect the in vivo biology of MLL-ENL leukemia with respect to Flt3 requirement. We conclude that wt Flt3 plays a role in leukemia initiation in vivo, which is, however, not universal.
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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：
50.3
作者：
Armstrong, SA;Kung, AL;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
20.3
作者：
Faber, Joerg;Krivtsov, Andrei V.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
4 号染色体上的数量性状基因座通过调节 TGF-β2 反应性影响造血干细胞和祖细胞的循环。
影响因子：
4.4
作者：
Avagyan, Serine;Glouchkova, Ludmila;Choi, Juhyun;Snoeck, Hans-Willem
通讯作者：
Snoeck, Hans-Willem
影响因子：
3.7
作者：
Albouhair S;Morgado E;Lavau C
通讯作者：
Lavau C