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Lookup NU author(s): Professor Olaf Heidenreich
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© 2022 American Society of Hematology. 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.
Author(s): Schnoeder TM, Schwarzer A, Jayavelu AK, Hsu C-J, Kirkpatrick J, Dohner K, Perner F, Eifert T, Huber N, Arreba-Tutusaus P, Dolnik A, Assi SA, Nafria M, Jiang L, Dai Y-T, Chen Z, Chen S-J, Kellaway SG, Ptasinska A, Ng ES, Stanley EG, Elefanty AG, Buschbeck M, Bierhoff H, Brodt S, Matziolis G, Fischer K-D, Hochhaus A, Chen C-W, Heidenreich O, Mann M, Lane SW, Bullinger L, Ori A, von Eyss B, Bonifer C, Heidel FH
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2022
Volume: 139
Issue: 7
Pages: 1080-1097
Print publication date: 17/02/2022
Online publication date: 27/10/2022
Acceptance date: 07/10/2021
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
URL: https://doi.org/10.1182/blood.2021012778
DOI: 10.1182/blood.2021012778
PubMed id: 34695195
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