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DUX4-r 在急性淋巴细胞白血病中发挥依赖于 GTF2I 的新功能活性。

DUX4-r exerts a neomorphic activity that depends on GTF2I in acute lymphoblastic leukemia.

机构信息

Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy.

Center for Omics Sciences, IRCCS Ospedale San Raffaele, 20132 Milano, Italy.

出版信息

Sci Adv. 2023 Sep 15;9(37):eadi3771. doi: 10.1126/sciadv.adi3771.

DOI:10.1126/sciadv.adi3771
PMID:37713484
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10881058/
Abstract

Translocations producing rearranged versions of the transcription factor double homeobox 4 (DUX4-r) are one of the most frequent causes of B cell acute lymphoblastic leukemia (B-ALL). DUX4-r retains the DNA binding domain of wild-type DUX4 but is truncated on the C-terminal transcription activation domain. The precise mechanism through which DUX4-r causes leukemia is unknown, and no targeted therapy is currently available. We found that the rearrangement leads to both a loss and a gain of function in DUX4-r. Loss of CBP/EP300 transcriptional coactivator interaction leads to an inability to bind and activate repressed chromatin. Concurrently, a gain of interaction with the general transcription factor 2 I (GTF2I) redirects DUX4-r toward leukemogenic targets. This neomorphic activity exposes an Achilles' heel whereby DUX4-r-positive leukemia cells are exquisitely sensitive to GTF2I targeting, which inhibits DUX4-r leukemogenic activity. Our work elucidates the molecular mechanism through which DUX4-r causes leukemia and suggests a possible therapeutic avenue tailored to this B-ALL subtype.

摘要

产生转录因子双同源盒 4（DUX4-r）重排版本的易位是 B 细胞急性淋巴细胞白血病（B-ALL）最常见的原因之一。DUX4-r 保留了野生型 DUX4 的 DNA 结合结构域，但在 C 端转录激活结构域被截断。DUX4-r 导致白血病的确切机制尚不清楚，目前也没有靶向治疗方法。我们发现该重排导致 DUX4-r 既有功能丧失又有功能获得。与 CBP/EP300 转录共激活因子相互作用的丧失导致无法结合并激活受抑制的染色质。同时，与一般转录因子 2 I（GTF2I）的相互作用增加将 DUX4-r 重新导向白血病相关靶点。这种新的活性暴露出一个阿喀琉斯之踵，即 DUX4-r 阳性白血病细胞对 GTF2I 靶向治疗非常敏感，这抑制了 DUX4-r 的白血病活性。我们的工作阐明了 DUX4-r 导致白血病的分子机制，并提出了针对这种 B-ALL 亚型的可能治疗途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/3307c7337ee7/sciadv.adi3771-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/5bc30574a92c/sciadv.adi3771-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/a55ebc60e03c/sciadv.adi3771-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/eeee8b0de8e7/sciadv.adi3771-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/5d5ab1eed09a/sciadv.adi3771-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/8358986b31a5/sciadv.adi3771-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/3307c7337ee7/sciadv.adi3771-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/5bc30574a92c/sciadv.adi3771-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/a55ebc60e03c/sciadv.adi3771-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/eeee8b0de8e7/sciadv.adi3771-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/5d5ab1eed09a/sciadv.adi3771-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/8358986b31a5/sciadv.adi3771-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd50/10881058/3307c7337ee7/sciadv.adi3771-f6.jpg

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