PNAS：白血病中BAALC基因过度激活

近日，研究人员发现BAALC基因在急性白血病细胞过度激活，这一发现可能白血病治疗提供一个预后指标。

这项研究发现BAALC过度表达是由单核苷酸多态性引发的，单核苷酸多态性开启基因的的表达，当基因关闭时，单核苷酸多态性允许不同的分子保持该基因的运行。

分子生物学和癌症遗传学专家、首席研究员Albert de la Chapelle博士说：我们想强调的是单核苷酸多态性并不提高我们患白血病的风险，但它易引发BAALC基因的过度表达，后者与白血病的发展和治疗反应不佳有关。

具体来说，单核苷酸多态性引起的DNA变化最终活化RUNX1分子，研究人员发现RUNX1蛋白水平高的患者BAALC基因表达水平高，而RUNX1低表达的患者BAALC基因表达也低。

研究论文发表在PNAS杂志上，证实了单核苷酸多态性可能是一个有用的预后指标，能用来指导急性白血病患者的治疗。

doi:10.1073/pnas.1203756109
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Heritable polymorphism predisposes to high BAALC expression in acute myeloid leukemia

Ann-Kathrin Eisfelda, Guido Marcuccia, Sandya Liyanarachchia, Konstanze D?hnerb, Sebastian Schwinda, Kati Maharrya,c, et al.

Overexpression of the brain and acute leukemia, cytoplasmic (BAALC) gene is implicated in myeloid leukemogenesis and associated with poor outcome in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. Additionally, high BAALC expression occurs in glioblastoma, melanoma, and childhood gastrointestinal stroma tumors, suggesting an oncogenic role for BAALC. However, the mechanisms underlying the deregulated expression are unknown. We hypothesized that a common heritable genetic feature located in cis might account for overexpression of BAALC in an allele-specific manner. By sequencing the genomic region of BAALC we identified nine informative single nucleotide polymorphisms (SNPs) and tested them for a possible association with BAALC expression levels. We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. The association of high BAALC expression with the T allele and its correlations with RUNX1 expresser status are shown in vivo in a test set (n = 253) and validation set (n = 105) of samples from cytogenetically normal AML patients from different populations. Thus, we identify a heritable genomic feature predisposing to overexpression of an oncogene, thereby possibly leading to enhanced AML leukemogenesis. Our findings further suggest that genomic variants might become useful tools in the practice of personalized medicine.