Abstract
In an effort to identify novel drugs targeting fusion-oncogene-induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE)-driven AML, we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein that is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO+ leukemic stem cells.
© 2022 by The American Society of Hematology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Self Renewal
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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Gene Expression Regulation, Leukemic*
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology*
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Humans
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology*
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Mice
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Phospholipase C gamma / genetics
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Phospholipase C gamma / metabolism*
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Proteome
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RUNX1 Translocation Partner 1 Protein / genetics
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RUNX1 Translocation Partner 1 Protein / metabolism*
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Transcriptome
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Translocation, Genetic
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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Oncogene Proteins, Fusion
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Proteome
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RUNX1 Translocation Partner 1 Protein
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PLCG1 protein, human
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Phospholipase C gamma