Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling
Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling
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DOI：
10.1073/pnas.0511150103
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发表时间：
2006-02-28
影响因子：
11.1
通讯作者：
Orkin, SH
中科院分区：
文献类型：
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作者：
Bourquin, JP;Subramanian, A;Orkin, SH
唐氏综合征（DS）患者易发生急性巨核细胞白血病（AMKL），其特征是由于体细胞突变而表达截短的GATA 1转录因子蛋白（GATA 1）。在非DS患者中，DS-AMKL的治疗结局比AMKL更有利。为了深入了解AMKL的基因表达差异，我们比较了24个DS和39个非DS AMKL样本。我们发现非DS-AMKL样品聚集在两组中，其特征在于HOX/TALE家族成员表达的差异。这两组都不同于DS-AMKL，不依赖于21号染色体基因表达。为了探索GATA 1转录组的改变，我们使用跨物种比较与GATA 1表达调节的基因在小鼠红系前体细胞。在小鼠系统中，GATA 1诱导后被抑制的基因，最显著的是加塔-2、MYC和KIT，在DS-AMKL中表现出表达增加，表明GATA 1不能抑制这类基因。在鼠系统中，只有一部分在GATA 1诱导后上调的基因在DS-AMKL中表达增加，包括GATA 1和BACH 1，这是位于21号染色体上的巨核细胞分化的可能负调节因子。令人惊讶的是，21号染色体基因RUNX 1（一种已知的巨核细胞生成调节因子）的表达在DS-AMKL中没有升高。我们的研究结果确定了不同AMKL实体的相关特征，并提供了与这些相关白血病相关的基因表达变化的见解。
Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.