| Literature DB >> 34695195 |
Tina M Schnoeder1, Adrian Schwarzer2,3, Ashok Kumar Jayavelu4, Chen-Jen Hsu1, Joanna Kirkpatrick5, Konstanze Döhner6, Florian Perner1,7, Theresa Eifert1, Nicolas Huber1, Patricia Arreba-Tutusaus8, Anna Dolnik9, Salam A Assi10, Monica Nafria10, Lu Jiang11, Yu-Ting Dai11, Zhu Chen11, Sai-Juan Chen11, Sophie G Kellaway10, Anetta Ptasinska10, Elizabeth S Ng12, Edouard G Stanley12,13, Andrew G Elefanty12, Marcus Buschbeck14, Holger Bierhoff15, Steffen Brodt16, Georg Matziolis16, Klaus-Dieter Fischer17, Andreas Hochhaus18, Chun-Wei Chen19, Olaf Heidenreich20,21, Matthias Mann4, Steven W Lane22, Lars Bullinger9, Alessandro Ori5, Björn von Eyss5, Constanze Bonifer10, Florian H Heidel1,5,18.
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.Entities:
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Year: 2022 PMID： 34695195 PMCID： PMC8854675 DOI： 10.1182/blood.2021012778
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 25.476