Protein phosphatase 4 regulatory subunit 2 (PPP4R2) is recurrently deleted in acute myeloid leukemia and required for efficient DNA double strand break repair
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Julia K. Herzig1, Lars Bullinger1, Alpaslan Tasdogan2,6, Philipp Zimmermann1, Martin Schlegel1, Veronica Teleanu1, Daniela Weber1, Frank G. Rücker1, Peter Paschka1, Anna Dolnik1, Edith Schneider1, Florian Kuchenbauer1, Florian H. Heidel4,5, Christian Buske3, Hartmut Döhner1, Konstanze Döhner1,* and Verena I. Gaidzik1,*
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
2Institute of Immunology, Ulm University, Ulm, Germany
3Institute of Experimental Cancer Research, University Hospital of Ulm, Ulm, Germany
4Leibniz Institute on Aging–Fritz Lipmann Institute, Jena, Germany
5Innere Medizin II, Hämatologie und Onkologie, Universitätsklinikum Jena, Jena, Germany
6Current/Present address: Children’s Medical Center Research Institute, UT Southwestern, Dallas, TX, USA
*These authors contributed equally to this work
Verena I. Gaidzik, email: Verena.Gaidzik@uniklinik-ulm.de
Keywords: AML, gene deletion, 3p, PPP4R2, DNA repair
Received: June 16, 2017 Accepted: September 03, 2017 Published: September 21, 2017
We have previously identified a recurrent deletion at chromosomal band 3p14.1-p13 in patients with acute myeloid leukemia (AML). Among eight protein-coding genes, this microdeletion affects the protein phosphatase 4 regulatory subunit 2 (PPP4R2), which plays an important role in DNA damage response (DDR). Investigation of mRNA expression during murine myelopoiesis determined that Ppp4r2 is higher expressed in more primitive hematopoietic cells. PPP4R2 expression in primary AML samples compared to healthy bone marrow was significantly lower, particularly in patients with 3p microdeletion or complex karyotype. To identify a functional role of PPP4R2 in hematopoiesis and leukemia, we genetically inactivated Ppp4r2 by RNAi in murine hematopoietic stem and progenitor cells and murine myeloid leukemia. Furthermore, we ectopically expressed PPP4R2 in a deficient human myeloid leukemic cell line. While PPP4R2 is involved in DDR of both hematopoietic and leukemic cells, our findings indicate that PPP4R2 deficiency impairs de-phosphorylation of phosphorylated key DDR proteins KRAB-domain associated protein 1 (pKAP1), histone variant H2AX (γH2AX), tumor protein P53 (pP53), and replication protein A2 (pRPA2). Potential impact of affected DNA repair processes in primary AML cases with regard to differential PPP4R2 expression or 3p microdeletion is also supported by our results obtained by gene expression profiling and whole exome sequencing. Impaired DDR and increased DNA damage by PPP4R2 suppression is one possible mechanism by which the 3p microdeletion may contribute to the pathogenesis of AML. Further studies are warranted to determine the potential benefit of inefficient DNA repair upon PPP4R2 deletion to the development of therapeutic agents.
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