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| Item Type: | Article |
|---|---|
| Title: | PLCG1 is required for AML1-ETO leukemia stem cell self-renewal |
| Creators: |
Schnoeder, T.M., Schwarzer, A., Jayavelu, A.K., Hsu, C.J., Kirkpatrick, J.  ORCID: https://orcid.org/0000-0001-9291-7294, Döhner, K., Perner, F., Eifert, T., Huber, N., Arreba-Tutusaus, P., Dolnik, A., Assi, S.A. ORCID: https://orcid.org/0000-0001-5634-1347, Nafria, M. ORCID: https://orcid.org/0000-0002-5329-7966, Jiang, L., Dai, Y.T. ORCID: https://orcid.org/0000-0001-8275-2115, Chen, Z., Chen, S.J., Kellaway, S.G. ORCID: https://orcid.org/0000-0002-4011-7460, Ptasinska, A., Ng, E.S. ORCID: https://orcid.org/0000-0002-7970-8129, Stanley, E.G., Elefanty, A.G. ORCID: https://orcid.org/0000-0001-6448-8314, Buschbeck, M., Bierhoff, H., Brodt, S. ORCID: https://orcid.org/0000-0003-1286-8766, Matziolis, G., Fischer, K.D., Hochhaus, A., Chen, C.W. ORCID: https://orcid.org/0000-0002-8737-6830, Heidenreich, O. ORCID: https://orcid.org/0000-0001-5404-6483, Mann, M., Lane, S.W. ORCID: https://orcid.org/0000-0002-8050-6209, Bullinger, L. ORCID: https://orcid.org/0000-0002-5890-5510, Ori, A. ORCID: https://orcid.org/0000-0002-3046-0871, von Eyss, B. ORCID: https://orcid.org/0000-0002-4731-6841, Bonifer, C. and Heidel, F. ORCID: https://orcid.org/0000-0003-2438-1955
|
| 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 |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 139 |
| Number: | 7 |
| Page Range: | 1080-1097 |
| Date: | 17 February 2022 |
| Additional Information: | Copyright © 2022 by The American Society of Hematology |
| Official Publication: | https://doi.org/10.1182/blood.2021012778 |
| PubMed: | View item in PubMed |
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