Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models
Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models
复制标题
DOI：
10.1182/blood-2010-02-270181
复制
发表时间：
2011-01-06
期刊：
影响因子：
20.3
通讯作者：
Kitamura, Toshio
中科院分区：
文献类型：
--
作者：
Kato, Naoko;Kitaura, Jiro;Kitamura, Toshio
在5%-14%的急性髓性白血病（AML）患者的白血病细胞中发现了两种类型的转录因子CCAAT增强子结合蛋白α（C/EBP α）突变：表达显性阴性p30的N端突变和碱性亮氨酸拉链结构域的C端突变。我们的研究结果表明，在骨髓增生异常综合征后的AML中观察到一个等位基因的C/EBP α突变，而在新发AML中观察到两个等位基因的突变。与N-末端移码突变体（C/EBP α-N（m））转导的细胞不同，C-末端突变体（C/EBP α-C（m））转导的细胞单独在骨髓移植后4-12个月在小鼠中诱导AML伴白细胞减少症。两种突变体的共表达诱导AML，伴有显著的白细胞增多和较短的淋巴细胞。有趣的是，C/EBP α-C（m）与Flt 3激活突变体Flt 3-ITD在诱导AML中协同作用。此外，C/EBP α-C（m）强烈阻断32 Dcl 3细胞的髓样分化，表明其在白血病发生中的II类突变样作用。尽管C/EBP α-C（m）未能抑制野生型C/EBP α的转录活性，但它抑制了C/EBP α和PU. 1之间的协同效应。另一方面，C/EBP α-N（m）在不存在PU. 1的情况下抑制C/EBP α活化，尽管C/EBP α-N（m）产生的p30蛋白表达水平低。因此，2种类型的C/EBP α突变涉及白血病发生，涉及不同的和合作的分子机制。（血。2011;117（1）：221-233）
Two types of mutations of a transcription factor CCAAT-enhancer binding protein alpha(C/EBP alpha) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBP alpha in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBP alpha-N(m))-transduced cells, a C-terminal mutant (C/EBP alpha-C(m))-transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBP alpha-C(m) collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBP alpha-C(m) strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBP alpha-C(m) failed to inhibit transcriptional activity of wild-type C/EBP alpha, it suppressed the synergistic effect between C/EBP alpha and PU.1. On the other hand, C/EBP alpha-N(m) inhibited C/EBP alpha activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBP alpha-N(m). Thus, 2 types of C/EBP alpha mutations are implicated in leukemogenesis, involving different and cooperating molecular mechanisms. (Blood. 2011;117(1):221-233)