MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia
| Autor: | Aishwarya Kulkarni, Meenakshi Venkatasubramanian, Svetlana S. Itskovich, Nathan Salomonis, Lynn Lee, Mikaela R. Berger, Mark Wunderlich, Matthew Burwinkel, Arun Gurunathan, Jason Clark, Kashish Chetal, Ashish R. Kumar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Science General Physics and Astronomy RNA-binding protein Biology General Biochemistry Genetics and Molecular Biology Targeted therapy 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases medicine lcsh:Science Gene neoplasms Multidisciplinary Alternative splicing Intron General Chemistry DOT1L medicine.disease Leukemia 030104 developmental biology 030220 oncology & carcinogenesis RNA splicing Cancer research lcsh:Q |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) |
| ISSN: | 2041-1723 |
| Popis: | Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A. We finally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins. |
| Databáze: | OpenAIRE |
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