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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Apoptosis / genetics
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Bone Marrow Transplantation
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Cell Line, Tumor
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Datasets as Topic
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Gene Expression Regulation, Neoplastic*
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Gene Knockdown Techniques
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Gene Rearrangement
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Histone-Lysine N-Methyltransferase / genetics
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Humans
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Introns / genetics
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Leukemia / drug therapy
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Leukemia / genetics*
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Leukemia / pathology
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Mice
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Mice, Knockout
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Oncogene Proteins, Fusion / genetics*
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Primary Cell Culture
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RNA, Small Interfering / metabolism
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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RNA-Seq
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Transplantation Chimera
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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DNA-Binding Proteins
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MBNL1 protein, human
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MLL-AF9 fusion protein, human
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Mbnl1 protein, mouse
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Oncogene Proteins, Fusion
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RNA, Small Interfering
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RNA-Binding Proteins
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Myeloid-Lymphoid Leukemia Protein
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DOT1L protein, human
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Histone-Lysine N-Methyltransferase
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Setd1A protein, human