Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of the TAF4 histone-fold fragment can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.

中文翻译：

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以 MYB 为目标并抑制急性髓性白血病的 TFIID-SAGA 扰动。

靶向一般共激活因子是一种新兴的干扰致癌转录因子 (TF) 的策略。然而，共激活因子扰动通常会通过影响大量转录因子而导致多效性效应。在这里，我们确定 TAF12（TFIID 和 SAGA 共激活因子复合物的一个亚基）是急性髓性白血病 (AML) 进展的选择性要求。我们将这种依赖性追溯到 TAF12/TAF4 组蛋白折叠异二聚体与 MYB 的反式激活域之间的直接相互作用，MYB 是一种在白血病发生中具有既定作用的 TF。TAF4 组蛋白折叠片段的异位表达可以有效抑制细胞中的 TAF12，抑制 MYB，并使小鼠的 AML 消退。我们的研究揭示了一种在 AML 中有效抑制 MYB 的策略，并强调了如何通过靶向一般共激活因子复合物来选择性地中和致癌 TF。