Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1
Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1
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DOI：
10.1038/ng1361
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发表时间：
2004-06-01
期刊：
影响因子：
30.8
通讯作者：
Tenen, DG
中科院分区：
文献类型：
--
作者：
Rosenbauer, F;Wagner, K;Tenen, DG
转录因子被认为在急性髓性白血病（AML）中具有主导作用。这一想法得到了基因敲除小鼠分析的支持，这些小鼠发现了几种转录因子在正常造血中的关键作用（1），以及白血病个体的转录因子经常下调或突变（2）。然而，基因敲除动物的分析没有显示废除的转录因子和AML的发病机制之间的直接联系。Sfpi 1编码谱系特异性转录因子PU.1，是正常骨髓和淋巴发育所必需的（3，4）。我们发现，与携带Sfpi 1纯合或杂合缺失的小鼠不同，携带将PU.1表达降低至正常水平20%的亚型Sfpi 1等位基因的小鼠发生AML。与完全或50%损失不同，80%的PU.1损失诱导癌前状态，其特征在于异常前体池的积累，保留对G-CSF的响应性，同时破坏M-和GM-CSF途径。恶性转化与高频率的克隆性染色体改变有关。逆转录病毒恢复PU.1表达挽救了突变祖细胞和AML母细胞的髓样分化。这些结果表明，紧密分级减少，而不是完全丢失，谱系不可或缺的转录因子可以诱导AML。
Transcription factors are believed to have a dominant role in acute myeloid leukemia (AML). This idea is supported by analysis of gene-knockout mice, which uncovered crucial roles of several transcription factors in normal hematopoiesis(1), and of individuals with leukemia, in whom transcription factors are frequently downregulated or mutated(2). However, analysis of knockout animals has not shown a direct link between abrogated transcription factors and the pathogenesis of AML. Sfpi1, encoding the lineage-specific transcription factor PU.1, is indispensable for normal myeloid and lymphoid development(3,4). We found that mice carrying hypomorphic Sfpi1 alleles that reduce PU.1 expression to 20% of normal levels, unlike mice carrying homo- or heterozygous deletions of Sfpi1, developed AML. Unlike complete or 50% loss, 80% loss of PU.1 induced a precancerous state characterized by accumulation of an abnormal precursor pool retaining responsiveness to G-CSF with disruption of M- and GM-CSF pathways. Malignant transformation was associated with a high frequency of clonal chromosomal changes. Retroviral restoration of PU.1 expression rescued myeloid differentiation of mutant progenitors and AML blasts. These results suggest that tightly graded reduction, rather than complete loss, of a lineage-indispensable transcription factor can induce AML.