Academic Journal
Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma
| العنوان: | Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma |
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| المؤلفون: | Trasanidis, N., Katsarou, A., Ponnusamy, K., Shen, Y.A., Kostopoulos, I.V., Bergonia, B., Keren, K., Reema, P., Xiao, X., Szydlo, R. M., Sabbattini, P., Roberts, I., Auner, H., Naresh, K., Chaidos, A., Wang, T.L., Magnani, L., Caputo, V., Karadimitris, A. |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2022 |
| المجموعة: | LSBU Research Open (London South Bank University) |
| الوصف: | Understanding the biological and clinical impact ofcopy number aberrations (CNA)for the development of precision therapies in cancer remains anunmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNAconferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although severalgenes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MMpatient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapystrategies in multiple myeloma and other types of cancer. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| Relation: | https://openresearch.lsbu.ac.uk/download/ec67f15193b92789a4d58aa36ae305a6ad19c0a6e59ebcbc053e33bb6fad69a5/13953823/blood.2021014391.pdf; https://doi.org/10.1182/blood.2021014391; Trasanidis, N., Katsarou, A., Ponnusamy, K., Shen, Y.A., Kostopoulos, I.V., Bergonia, B., Keren, K., Reema, P., Xiao, X., Szydlo, R. M., Sabbattini, P., Roberts, I., Auner, H., Naresh, K., Chaidos, A., Wang, T.L., Magnani, L., Caputo, V. and Karadimitris, A. (2022). Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma. Blood. https://doi.org/10.1182/blood.2021014391 |
| DOI: | 10.1182/blood.2021014391 |
| الاتاحة: | https://openresearch.lsbu.ac.uk/item/8z12x https://openresearch.lsbu.ac.uk/download/ec67f15193b92789a4d58aa36ae305a6ad19c0a6e59ebcbc053e33bb6fad69a5/13953823/blood.2021014391.pdf https://doi.org/10.1182/blood.2021014391 |
| Rights: | CC BY 4.0 |
| رقم الانضمام: | edsbas.5DBEB16C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1182/blood.2021014391 |
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