Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.

中文翻译：

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一个独特的核心调控模块强制 KMT2A 重排白血病中的癌基因表达

具有 KMT2A (MLL) 重排的急性髓性白血病的特点是基因表达和增强子结构的特定模式，这意味着独特的核心转录调控电路。在这里，我们将转录因子 MEF2D 和 IRF8 鉴定为 KMT2A 重排 AML 的选择性转录依赖性，其中 MEF2D 与其旁系同源物 MEF2C 显示部分冗余功能。快速转录因子降解，随后测量全基因组转录率和超分辨率显微镜显示，MEF2D 和 IRF8 形成独特的核心调控模块，具有狭窄的直接转录程序，包括激活关键癌基因 MYC、HOXA9 和 BCL2。