Transcription factors (TFs) orchestrating lineage-development often control genes required for cellular survival. However, it is not well understood how cells survive when such TFs are lost, for example in cancer. PU.1 is an essential TF for myeloid fate, and mice with downregulated PU.1 levels develop acute myeloid leukemia (AML). Combining a multi-omics approach with a functional genetic screen, we reveal that PU.1-downregulated cells fundamentally change their survival control from cytokine-driven pathways to overexpression of an autophagy-predominated stem cell gene program, for which we also find evidence in human AML. Control of this program involves redirected chromatin occupancy of the PU.1 partner TF Runx1 to a lineage-inappropriate binding site repertoire. Hence, genomic reallocation of TF binding upon loss of a partner TF can act as a pro-oncogenic failsafe mechanism by sustaining cell survival during leukemogenesis.

中文翻译：

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PU.1 伴侣转录因子 RUNX1 结合的重新分布可确保白血病发生过程中的细胞存活。


协调谱系发育的转录因子 （TFs） 通常控制细胞存活所需的基因。然而，目前尚不清楚当此类 TF 丢失时，例如在癌症中，细胞如何存活。PU.1 是髓系命运所必需的 TF，PU.1 水平下调的小鼠会发展为急性髓系白血病 （AML）。将多组学方法与功能遗传学筛选相结合，我们揭示了 PU.1 下调的细胞从根本上改变了它们的生存控制，从细胞因子驱动的途径转变为自噬为主的干细胞基因程序的过表达，我们在人类 AML 中也发现了证据。该程序的控制涉及将 PU.1 伴侣 TF Runx1 的染色质占据重定向到谱系不适当的结合位点库。因此，在伴侣 TF 丢失时 TF 结合的基因组重新分配可以通过维持白血病发生过程中的细胞存活来充当促癌故障安全机制。