Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis
Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis
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DOI：
10.1172/jci200522725
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发表时间：
2005-04-01
影响因子：
15.9
通讯作者：
Nosaka, T
中科院分区：
文献类型：
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作者：
Ono, R;Nakajima, H;Nosaka, T
子宫内11q23基因易位导致的混合谱系白血病（MLL）融合产物参与白血病发生和婴儿急性白血病的机制尚不清楚。MLL融合蛋白是否足以在没有额外遗传改变的情况下诱导急性白血病，目前仍存在争议，尽管众所周知，一生中积累的超过1种遗传疾病通常会导致癌变。在这里，我们证明了MLL-SEPT6的融合伴侣介导的同质寡聚化对于体外造血祖细胞的永生化是必不可少的。MLL-SEPT6在小鼠中诱导具有长潜伏期的骨髓增生性疾病，而不是急性白血病，这意味着继发性遗传毒性事件是白血病发生的必要条件。我们利用MLL融合蛋白在体外和体内建立了白血病发生的模型系统，其中激活的fms样受体酪氨酸激酶3 （FLT3）与MLL- sept6一起不仅在体外转化造血祖细胞，而且在体内诱导短潜伏期急性双表型或髓系白血病。在这些系统中，MLL-ENL，另一种似乎作为单体的融合产物，也与活化的FLT3一起诱导体外转化和体内白血病发生。这些发现为MLL融合蛋白介导的多步骤白血病发生提供了直接证据，可能适用于开发直接的MLL融合靶向治疗。
The mechanisms by which mixed-lineage leukemia (MLL) fusion products resulting from in utero translocations in 11q23 contribute to leukemogenesis and infant acute leukemia remain elusive. It is still controversial whether the MLL fusion protein is sufficient to induce acute leukemia without additional genetic alterations, although carcinogenesis in general is known to result from more than I genetic disorder accumulating during a lifetime. Here we demonstrate that the fusion partner-mediated homo-oligomerization of MLL-SEPT6 is essential to immortalize hematopoietic progenitors in vitro. MLL-SEPT6 induced myeloproliferative disease with long latency in mice, but not acute leukemia, implying that secondary genotoxic events are required to develop leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3 (FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. In these systems, MLL-ENL, another type of the fusion product that seems to act as a monomer, also induced the transformation in vitro and leukemogenesis in vivo in concert with activated FLT3. These findings show direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.