Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia
| Autor: | Andrew J.K. Williamson, Chinmay Munje, Sarah Baker, Samuel J. Taylor, Marie Hodges, Steven Knapper, Michelle Doyle, Amanda F. Gilkes, Namrata Rastogi, Alex Tonks, Paul S. Hole, Andrew Pierce, Bader Alanazi, Richard Lawrence Darley, Anthony D. Whetton |
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| Rok vydání: | 2019 |
| Předmět: |
Proteomics
Myeloid Adult Male 0301 basic medicine Cancer Research Adolescent Proteome CD34 Antigens CD34 Biology Article Transcriptome 03 medical and health sciences 0302 clinical medicine AML hemic and lymphatic diseases medicine S100A4 Humans S100 Calcium-Binding Protein A4 Transcriptomics Transcription factor neoplasms Cells Cultured Aged Cell Proliferation Cell Nucleus Leukemia Manchester Cancer Research Centre ResearchInstitutes_Networks_Beacons/mcrc Myeloid leukemia Hematology Middle Aged medicine.disease Leukemia Myeloid Acute Haematopoiesis 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Neoplastic Stem Cells Cancer research Female |
| Zdroj: | Whetton, A 2019, ' Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia ', Leukemia . https://doi.org/10.1038/s41375-019-0596-4 Leukemia |
| ISSN: | 0887-6924 |
| DOI: | 10.1038/s41375-019-0596-4 |
| Popis: | Inappropriate localization of proteins can interfere with normal cellular function and drive tumor development. To understand how this contributes to the development of acute myeloid leukemia (AML), we compared the nuclear proteome and transcriptome of AML blasts with normal human CD34+ cells. Analysis of the proteome identified networks and processes that significantly affected transcription regulation including misexpression of 11 transcription factors with seven proteins not previously implicated in AML. Transcriptome analysis identified changes in 40 transcription factors but none of these were predictive of changes at the protein level. The highest differentially expressed protein in AML nuclei compared with normal CD34+ nuclei (not previously implicated in AML) was S100A4. In an extended cohort, we found that over-expression of nuclear S100A4 was highly prevalent in AML (83%; 20/24 AML patients). Knock down of S100A4 in AML cell lines strongly impacted their survival whilst normal hemopoietic stem progenitor cells were unaffected. These data are the first analysis of the nuclear proteome in AML and have identified changes in transcription factor expression or regulation of transcription that would not have been seen at the mRNA level. These data also suggest that S100A4 is essential for AML survival and could be a therapeutic target in AML. |
| Databáze: | OpenAIRE |
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