Regulatory mechanisms and context-dependent roles of TAL1 in T-cell acute lymphoblastic leukemia
| Autor: | Jolynn Zu Lin Ong, Tze King Tan, Lu Wang, Shi Hao Tan, Takaomi Sanda |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 109, Iss 5 (2023) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.2023.283450 |
| Popis: | T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy derived from thymic T-cell precursors. Approximately 40-60% of T-ALL cases exhibit aberrant overexpression of the TAL1 oncogenic transcription factor. Here, we provide a comprehensive view of the TAL1-induced transcriptional program in human T-ALL cells using a rapid protein degradation system coupled with integrative approaches. Our study demonstrates that TAL1 targets can be classified into several groups, each of which exhibits unique gene expression kinetics, chromatin features, and regulatory mechanisms. Group A genes are highly dependent on TAL1, many of which are not expressed in normal T cells or TAL1-negative T-ALL cells, representing an oncogenic TAL1 signature. The TAL1 complex predominantly activates group A genes. TAL1’s effect is not replaceable with its regulatory partners GATA3 or RUNX1. In contrast, group B genes, many of which are generally expressed across different T-ALL subgroups, exhibit densely-connected chromatin-chromatin interactions and demonstrate the collaborative roles played by TAL1 with other transcription factors. Interestingly, TAL1 cooperates with NOTCH1 to regulate gene expression in TAL1-positive T-ALL cells, whereas it potentially antagonizes the NOTCH1-MYC pathway and leads to lethality in TAL1-negative/ TLX3-positive cells, demonstrating the context-dependent roles of TAL1. |
| Databáze: | Directory of Open Access Journals |
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