Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia
العنوان: | Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia |
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المؤلفون: | Alexander Thompson, Ivan Grishagin, Guy Sauvageau, Ken I. Mills, Janet J. Bijl, David Simpson, Glenda Dickson, Paul G. O’Reilly, Laura M. Kettyle, Charles-Étienne Lebert-Ghali |
المصدر: | Cancers Volume 11 Issue 12 Kettyle, L, Lebert-Ghali, C E, Grishagin, I, Dickson, G, O'Reilly, P, Simpson, D, Bijl, J, Mills, K, Sauvageau, G & Thompson, A 2019, ' Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia ', Cancers, vol. 11, no. 12, 2036 . https://doi.org/10.3390/cancers11122036 |
بيانات النشر: | Multidisciplinary Digital Publishing Institute, 2019. |
سنة النشر: | 2019 |
مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, HOXA cluster, pathways, MLL-rearrangement, Biology, leukemia maintenance, gene signature, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Fanconi anemia, hemic and lymphatic diseases, medicine, Progenitor cell, Gene, Wild type, Gene signature, medicine.disease, candidate drugs, Leukemia, Haematopoiesis, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, conditional deletion |
الوصف: | High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation. |
وصف الملف: | application/pdf |
اللغة: | English |
تدمد: | 2072-6694 |
DOI: | 10.3390/cancers11122036 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c51e120a68ba7d013ba4b3db99255675 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....c51e120a68ba7d013ba4b3db99255675 |
قاعدة البيانات: | OpenAIRE |
تدمد: | 20726694 |
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DOI: | 10.3390/cancers11122036 |