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AF10 易位驱动的急性白血病中 PZP 结构域的作用。

The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations.

机构信息

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.

Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

出版信息

Nat Commun. 2021 Jul 5;12(1):4130. doi: 10.1038/s41467-021-24418-9.

DOI:10.1038/s41467-021-24418-9
PMID:34226546
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8257627/
Abstract

Chromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10 into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10 binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10 promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10 function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10 downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10-dependent CALM-AF10-mediated leukemogenesis.

摘要

AF10（或 MLLT10）基因的染色体易位在急性白血病中经常发生。在这里，我们表明，在致白血病性 AF10 易位中持续受损或缺失的 AF10 的 PZP 结构域在阻断恶性转化中起着关键作用。将功能性 AF10 纳入致白血病性 CALM-AF10 融合中可防止融合在体外和体内的骨髓源性造血干/祖细胞中转化活性，并消除 CALM-AF10 介导的体内白血病发生。晶体学、生化和诱变研究表明，AF10 通过与组蛋白 H3 尾巴和 DNA 的多价接触与核小体核心颗粒结合，并在细胞中与染色质结合，与活性甲基化标记共定位并排除抑制性 H3K27me3 标记。AF10 促进 CALM-AF10 的核定位，并与染色质结合所必需。我们的数据表明，CALM-AF10 融合中 AF10 功能的破坏直接导致转化，而 AF10 的包含下调 Hoxa 基因并逆转细胞转化。我们的发现强调了 AF10 靶向染色质的分子机制，并提出了一个模型，用于解释 AF10 依赖性 CALM-AF10 介导的白血病发生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/404a469b92f7/41467_2021_24418_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/6093173d7183/41467_2021_24418_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/02ef6ca5ebda/41467_2021_24418_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/404a469b92f7/41467_2021_24418_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/aebbd28fc0e3/41467_2021_24418_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/f376c2c82616/41467_2021_24418_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/888c84cc9ee6/41467_2021_24418_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/a266cc44383f/41467_2021_24418_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/6093173d7183/41467_2021_24418_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/05beaf60fa1c/41467_2021_24418_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/04c0da18d644/41467_2021_24418_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/e943f2cfd987/41467_2021_24418_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/02ef6ca5ebda/41467_2021_24418_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a40/8257627/404a469b92f7/41467_2021_24418_Fig10_HTML.jpg

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