Expression, ChIP-chip, and ChIP-Seq data from REH and SEM leukemia cell lines [ChIP-Seq]

MLL-fusion proteins are potent inducers of cancer in hematopoietic cells, where they are known to cause changes in global gene expression. How MLL-fusion proteins interact with the genome has not been established, so we have limited understanding of the pathway by which these proteins generate aberrant gene expression programs. Here we describe how the MLL-AF4 protein occupies the genome in human leukemia cells and its striking effects on chromatin states. We find that the MLL-AF4 fusion protein selectively occupies regions of the genome that contain developmental regulatory genes important for hematopoietic stem cell identity and self-renewal. These MLL-AF4 bound regions have grossly altered chromatin structure, with histone modifications catalyzed by Trithorax Group (TrxG) proteins and Dot1 extending across unusually large domains. This indicates that a key feature of MLL-associated leukemogenesis is aberrant targeting of chromatin modifiers to regions of the genome controlling hematopoietic development. Our results define the direct targets of the MLL-fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in human cancer.

混合谱系白血病融合蛋白（MLL-fusion proteins）是造血细胞恶性转化的强效诱导因子，已知其可引发全局基因表达的改变。目前，此类融合蛋白与基因组的相互作用机制尚未阐明，因此我们对其介导异常基因表达程序的调控通路认知有限。本研究阐明了MLL-AF4融合蛋白在人类白血病细胞中的基因组结合模式，及其对染色质状态的显著调控效应。研究发现，MLL-AF4融合蛋白可选择性结合与造血干细胞身份维持及自我更新密切相关的发育调控基因所在的基因组区域。这些被MLL-AF4结合的基因组区域存在显著异常的染色质结构：由Trithorax组（Trithorax Group，TrxG）蛋白与Dot1催化的组蛋白修饰，会扩散至异常宽大的染色质结构域。上述结果表明，MLL相关白血病发生的关键特征之一，是染色质修饰因子被异常靶向至调控造血发育的基因组区域。本研究明确了MLL融合蛋白的直接靶标，揭示了表观遗传失调在白血病发生中的全局调控作用，并为人类癌症的治疗干预找到了新靶点。