MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia

Svetlana S. Itskovich, Arun Gurunathan, Jason Clark, Matthew Burwinkel, Mark Wunderlich, Mikaela R. Berger, Aishwarya Kulkarni, Kashish Chetal, Meenakshi Venkatasubramanian, Nathan Salomonis, Ashish R. Kumar and Lynn H. Lee ()
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Svetlana S. Itskovich: Cincinnati Children’s Hospital Medical Center
Arun Gurunathan: Cincinnati Children’s Hospital Medical Center
Jason Clark: Cincinnati Children’s Hospital Medical Center
Matthew Burwinkel: Cincinnati Children’s Hospital Medical Center
Mark Wunderlich: Cincinnati Children’s Hospital Medical Center
Mikaela R. Berger: University of Cincinnati School of Medicine
Aishwarya Kulkarni: University of Cincinnati
Kashish Chetal: Cincinnati Children’s Hospital Medical Center
Meenakshi Venkatasubramanian: University of Cincinnati
Nathan Salomonis: Cincinnati Children’s Hospital Medical Center
Ashish R. Kumar: Cincinnati Children’s Hospital Medical Center
Lynn H. Lee: University of Cincinnati School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15733-8

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