Absence of the transcription factor CCAAT enhancer binding protein α results in loss of myeloid identity in bcr/abl-induced malignancy
Absence of the transcription factor CCAAT enhancer binding protein α results in loss of myeloid identity in bcr/abl-induced malignancy
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DOI：
10.1073/pnas.0508143103
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发表时间：
2006-04-18
影响因子：
11.1
通讯作者：
Tenen, DG
中科院分区：
文献类型：
--
作者：
Wagner, K;Zhang, P;Tenen, DG
谱系决定转录因子CCAAT增强子结合蛋白α（C/EBP α）是髓样分化所必需的。C/EBP α的功能或表达降低常见于人类急性髓性白血病。然而，C/EBP α缺乏对白血病发生中成熟停滞的确切影响还不清楚。为了解决这个问题，我们使用了bcr/ab诱导的骨髓增生性疾病的小鼠移植模型。在C/EBP α（pos）胎肝细胞中表达bcr/abl导致慢性髓性白血病样疾病。令人惊讶的是，表达bcr/abl的C/EBP α（-/-）胎肝细胞在移植小鼠中未能诱导骨髓疾病，而是引起致命的可移植红白血病。因此，在C/EBP α（-/-）胎肝造血前体细胞中发现转录因子SCL和加塔-1的表达增加。与移植模型的发现一致，C/EBP α和加塔-1的表达呈负相关。Id 1是一种红细胞分化抑制剂，被鉴定为C/EBP α的关键直接靶点。通过RNA干扰下调Id 1损害C/EBP α诱导的粒细胞分化综上所述，我们的研究提供了证据表明，恶性造血祖细胞的髓系身份需要C/EBP α的残留表达。
The lineage-determining transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is required for myeloid differentiation. Decreased function or expression of C/EBP alpha is often found in human acute myeloid leukemia. However, the precise impact of C/EBP alpha deficiency on the maturation arrest in leukemogenesis is not well understood. To address this question, we used a murine transplantation model of a bcr/abl-induced myeloproliferative disease. The expression of bcr/abl in C/EBP alpha(pos) fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBP alpha(-/-) fetal liver cells failed to induce a myeloid disease in transplanted mice, but caused a fatal, transplantable erythroleukemia instead. Accordingly, increased expression of the transcription factors SCL and GATA-1 in hematopoietic precursor cells of C/EBP alpha(-/-) fetal livers was found. The mechanism for the lineage shift from myeloid to erythroid leukemia was studied in a bcr/abl-positive cell line. Consistent with findings of the transplant model, expression of C/EBP alpha and GATA-1 was inversely correlated. Id1, an inhibitor of erythroid differentiation, was identified as a critical direct target of C/EBP alpha. Down-regulation of Id1 by RNA interference impaired C/EBP alpha-induced granulocytic differentiation. Taken together, our study provides evidence that myeloid lineage identity of malignant hematopoietic progenitor cells requires the residual expression of C/EBP alpha.