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PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

Item Type:Article
Title:PLCG1 is required for AML1-ETO leukemia stem cell self-renewal
Creators Name:Schnoeder, T.M. and Schwarzer, A. and Jayavelu, A.K. and Hsu, C.J. and Kirkpatrick, J. and Döhner, K. and Perner, F. and Eifert, T. and Huber, N. and Arreba-Tutusaus, P. and Dolnik, A. and Assi, S.A. and Nafria, M. and Jiang, L. and Dai, Y.T. and Chen, Z. and Chen, S.J. and Kellaway, S.G. and Ptasinska, A. and Ng, E.S. and Stanley, E.G. and Elefanty, A.G. and Buschbeck, M. and Bierhoff, H. and Brodt, S. and Matziolis, G. and Fischer, K.D. and Hochhaus, A. and Chen, C.W. and Heidenreich, O. and Mann, M. and Lane, S.W. and Bullinger, L. and Ori, A. and von Eyss, B. and Bonifer, C. and Heidel, F.
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 de-regulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which 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 positive leukemic stem cells.
Keywords:Acute Myeloid Leukemia, Cell Self Renewal, Core Binding Factor Alpha 2 Subunit, Fusion Oncogene Proteins, Genetic Translocation, Hematopoietic Stem Cells, Leukemic Gene Expression Regulation, Neoplastic Stem Cells, Phospholipase C gamma, Proteome, RUNX1 Translocation Partner 1 Protein, Transcriptome, Animals, Mice
Publisher:American Society of Hematology
Page Range:1080-1097
Date:17 February 2022
Official Publication:https://doi.org/10.1182/blood.2021012778
PubMed:View item in PubMed

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