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

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.

SUBMITTER: Schnoeder TM 

PROVIDER: S-EPMC8854675 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Schnoeder Tina M TM   Schwarzer Adrian A   Jayavelu Ashok Kumar AK   Hsu Chen-Jen CJ   Kirkpatrick Joanna J   Döhner Konstanze K   Perner Florian F   Eifert Theresa T   Huber Nicolas N   Arreba-Tutusaus Patricia P   Dolnik Anna A   Assi Salam A SA   Nafria Monica M   Jiang Lu L   Dai Yu-Ting YT   Chen Zhu Z   Chen Sai-Juan SJ   Kellaway Sophie G SG   Ptasinska Anetta A   Ng Elizabeth S ES   Stanley Edouard G EG   Elefanty Andrew G AG   Buschbeck Marcus M   Bierhoff Holger H   Brodt Steffen S   Matziolis Georg G   Fischer Klaus-Dieter KD   Hochhaus Andreas A   Chen Chun-Wei CW   Heidenreich Olaf O   Mann Matthias M   Lane Steven W SW   Bullinger Lars L   Ori Alessandro A   von Eyss Björn B   Bonifer Constanze C   Heidel Florian H FH  

Blood 20220201 7

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,  ...[more]

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