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

Tina M Schnoeder; Adrian Schwarzer; Ashok Kumar Jayavelu; Chen-Jen Hsu; Joanna Kirkpatrick; Konstanze Döhner; Florian Perner; Theresa Eifert; Nicolas Huber; Patricia Arreba-Tutusaus; Anna Dolnik; Salam A Assi; Monica Nafria; Lu Jiang; Yu-Ting Dai; Zhu Chen; Sai-Juan Chen; Sophie G Kellaway; Anetta Ptasinska; Elizabeth S Ng; Edouard G Stanley; Andrew G Elefanty; Marcus Buschbeck; Holger Bierhoff; Steffen Brodt; Georg Matziolis; Klaus-Dieter Fischer; Andreas Hochhaus; Chun-Wei Chen; Olaf Heidenreich; Matthias Mann; Steven W Lane; Lars Bullinger; Alessandro Ori; Björn von Eyss; Constanze Bonifer; Florian Heidel

doi:10.1182/blood.2021012778

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

Tina M Schnoeder, Adrian Schwarzer, Ashok Kumar Jayavelu, Chen-Jen Hsu, Joanna Kirkpatrick, Konstanze Döhner, Florian Perner, Theresa Eifert, Nicolas Huber, Patricia Arreba-Tutusaus, Anna Dolnik, Salam A Assi, Monica Nafria, Lu Jiang, Yu-Ting Dai, Zhu Chen, Sai-Juan Chen, Sophie G Kellaway, Anetta Ptasinska, Elizabeth S NgEdouard G Stanley, Andrew G Elefanty, Marcus Buschbeck, Holger Bierhoff, Steffen Brodt, Georg Matziolis, Klaus-Dieter Fischer, Andreas Hochhaus, Chun-Wei Chen, Olaf Heidenreich, Matthias Mann, Steven W Lane, Lars Bullinger, Alessandro Ori, Björn von Eyss, Constanze Bonifer, Florian Heidel

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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.

Original language	English
Journal	Blood
Early online date	25 Oct 2021
DOIs	https://doi.org/10.1182/blood.2021012778
Publication status	E-pub ahead of print - 25 Oct 2021

Bibliographical note

Keywords

Biochemistry
Cell Biology
Hematology
Immunology

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10.1182/blood.2021012778Licence: None: All rights reserved

SchnoederT2021PLCG1
This research was originally published in Blood Online. Tina M. Schnoeder, Adrian Schwarzer, Ashok Kumar Jayavelu, Chen-Jen Hsu, Joanna Kirkpatrick, Konstanze Döhner, Florian Perner, Theresa Eifert, Nicolas Huber, Patricia Arreba-Tutusaus, Anna Dolnik, Salam A Assi, Monica Nafria, Lu Jiang, Yu-Ting Dai, Zhu Chen, Sai-Juan Chen, Sophie G. Kellaway, Anetta Ptasinska, Elizabeth S. Ng, Edouard G. Stanley, Andrew G. Elefanty, Marcus Buschbeck, Holger Bierhoff, Steffen Brodt, Georg Matziolis, Klaus-Dieter Fischer, Andreas Hochhaus, Chun-Wei Chen, Olaf Heidenreich, Matthias Mann, Steven W Lane, Lars Bullinger, Alessandro Ori, Björn von Eyss, Constanze Bonifer, Florian Heidel. PLCG1 is required for AML1-ETO leukemia stem cell self-renewal. Blood. Prepublished October 25, 2021; DOI 10.1182/blood.2021012778.
Accepted author manuscript, 2.03 MBLicence: None: All rights reserved

Cite this

Schnoeder, T. M., Schwarzer, A., Jayavelu, A. K., Hsu, C-J., Kirkpatrick, J., Döhner, K., Perner, F., Eifert, T., Huber, N., Arreba-Tutusaus, P., Dolnik, A., Assi, S. A., Nafria, M., Jiang, L., Dai, Y-T., Chen, Z., Chen, S-J., Kellaway, S. G., Ptasinska, A., ... Heidel, F. (2021). PLCG1 is required for AML1-ETO leukemia stem cell self-renewal. Blood. Advance online publication. https://doi.org/10.1182/blood.2021012778

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title = "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 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 = "Biochemistry, Cell Biology, Hematology, Immunology",

author = "Schnoeder, {Tina M} and Adrian Schwarzer and Jayavelu, {Ashok Kumar} and Chen-Jen Hsu and Joanna Kirkpatrick and Konstanze D{\"o}hner and Florian Perner and Theresa Eifert and Nicolas Huber and Patricia Arreba-Tutusaus and Anna Dolnik and Assi, {Salam A} and Monica Nafria and Lu Jiang and Yu-Ting Dai and Zhu Chen and Sai-Juan Chen and Kellaway, {Sophie G} and Anetta Ptasinska and Ng, {Elizabeth S} and Stanley, {Edouard G} and Elefanty, {Andrew G} and Marcus Buschbeck and Holger Bierhoff and Steffen Brodt and Georg Matziolis and Klaus-Dieter Fischer and Andreas Hochhaus and Chun-Wei Chen and Olaf Heidenreich and Matthias Mann and Lane, {Steven W} and Lars Bullinger and Alessandro Ori and Eyss, {Bj{\"o}rn von} and Constanze Bonifer and Florian Heidel",

note = "Copyright {\textcopyright} 2021 American Society of Hematology.",

year = "2021",

month = oct,

day = "25",

doi = "10.1182/blood.2021012778",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

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Schnoeder, TM, Schwarzer, A, Jayavelu, AK, Hsu, C-J, Kirkpatrick, J, Döhner, 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, Eyss, BV, Bonifer, C & Heidel, F 2021, 'PLCG1 is required for AML1-ETO leukemia stem cell self-renewal', Blood. https://doi.org/10.1182/blood.2021012778

TY - JOUR

T1 - PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

AU - Schnoeder, Tina M

AU - Schwarzer, Adrian

AU - Jayavelu, Ashok Kumar

AU - Hsu, Chen-Jen

AU - Kirkpatrick, Joanna

AU - Döhner, Konstanze

AU - Perner, Florian

AU - Eifert, Theresa

AU - Huber, Nicolas

AU - Arreba-Tutusaus, Patricia

AU - Dolnik, Anna

AU - Assi, Salam A

AU - Nafria, Monica

AU - Jiang, Lu

AU - Dai, Yu-Ting

AU - Chen, Zhu

AU - Chen, Sai-Juan

AU - Kellaway, Sophie G

AU - Ptasinska, Anetta

AU - Ng, Elizabeth S

AU - Stanley, Edouard G

AU - Elefanty, Andrew G

AU - Buschbeck, Marcus

AU - Bierhoff, Holger

AU - Brodt, Steffen

AU - Matziolis, Georg

AU - Fischer, Klaus-Dieter

AU - Hochhaus, Andreas

AU - Chen, Chun-Wei

AU - Heidenreich, Olaf

AU - Mann, Matthias

AU - Lane, Steven W

AU - Bullinger, Lars

AU - Ori, Alessandro

AU - Eyss, Björn von

AU - Bonifer, Constanze

AU - Heidel, Florian

PY - 2021/10/25

Y1 - 2021/10/25

N2 - 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.

AB - 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.

KW - Biochemistry

KW - Cell Biology

KW - Hematology

KW - Immunology

U2 - 10.1182/blood.2021012778

DO - 10.1182/blood.2021012778

M3 - Article

C2 - 34695195

SN - 0006-4971

JO - Blood

JF - Blood

ER -

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

Abstract

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