| Title: | Inherited blood cancer predisposition through altered transcription elongation |
| Journal: | Cell |
| Published: | 12 Jan 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38218188/ |
| DOI: | https://doi.org/10.1016/j.cell.2023.12.016 |
| URL: | http://www.cell.com/article/S009286742301348X/pdf |
Publication 8955
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Abstract
Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.</p>
13 Authors
- Jiawei Zhao
- Liam D Cato
- Uma P Arora
- Erik L Bao
- Samuel C Bryant
- Nicholas Williams
- Yuemeng Jia
- Seth R Goldman
- Jyoti Nangalia
- Michael A Erb
- Seychelle M Vos
- Scott A Armstrong
- Vijay G Sankaran
1 Application
| Application ID | Title |
|---|---|
| 31063 | Methodological extensions to estimate genetic heritability and shared risk factors for phenotypes of the UK Biobank |
Enabling scientific discoveries that improve human health