Different regulation of  PARP1, PARP2, PARP3  and  TRPM2  genes expression in acute myeloid leukemia cells

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Abstract

Background

Acute myeloid leukemia (AML) is a heterogenic lethal disorder characterized by the accumulation of abnormal myeloid progenitor cells in the bone marrow which results in hematopoietic failure. Despite various efforts in detection and treatment, many patients with AML die of this cancer. That is why it is important to develop novel therapeutic options, employing strategic target genes involved in apoptosis and tumor progression.

Methods

The aim of the study was to evaluate PARP1, PARP2, PARP3, and TRPM2 gene expression at mRNA level using qPCR method in the cells of hematopoietic system of the bone marrow in patients with acute myeloid leukemia, bone marrow collected from healthy patients, peripheral blood of healthy individuals, and hematopoietic stem cells from the peripheral blood after mobilization.

Results

The results found that the bone marrow cells of the patients with acute myeloid leukemia (AML) show overexpression of PARP1 and PARP2 genes and decreased TRPM2 gene expression. In the hematopoietic stem cells derived from the normal marrow and peripheral blood after mobilization, the opposite situation was observed, i.e. TRPM2 gene showed increased expression while PARP1 and PARP2 gene expression was reduced. We observed positive correlations between PARP1, PARP2, PARP3, and TRPM2 genes expression in the group of mature mononuclear cells derived from the peripheral blood and in the group of bone marrow-derived cells. In AML cells significant correlations were not observed between the expression of the examined genes. In addition, we observed that the reduced expression of TRPM2 and overexpression of PARP1 are associated with a shorter overall survival of patients, indicating the prognostic significance of these genes expression in AML.

Conclusions

Our research suggests that in physiological conditions in the cells of the hematopoietic system there is mutual positive regulation of PARP1, PARP2, PARP3, and TRPM2 genes expression. PARP1, PARP2, and TRPM2 genes at mRNA level deregulate in acute myeloid leukemia cells.

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Most cited references 22

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Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2.

Claudia A. Doege, Keiichi Inoue, Toru Yamashita … (2012)

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, our data, and also studies of Tet2-mutant human tumour cells, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.

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Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types.

Christopher Alvares, Eric Kaldjian, Sung Koo … (2010)

Poly (ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair and is implicated in pathways of tumorigenesis. PARP inhibitors have gained recent attention as rationally designed therapeutics for the treatment of several malignancies, particularly those associated with dysfunctional DNA repair pathways, including triple-negative breast cancer (TNBC). We investigated the PARP1 gene expression profile in surgical samples from more than 8,000 primary malignant and normal human tissues. PARP1 expression was found to be significantly increased in several malignant tissues, including those isolated from patients with breast, uterine, lung, ovarian, and skin cancers, and non-Hodgkin's lymphoma. Within breast infiltrating ductal carcinoma (IDC) samples tested, mean PARP1 expression was significantly higher relative to normal breast tissue, with over 30% of IDC samples demonstrating upregulation of PARP1, compared with 2.9% of normal tissues. Because of known DNA repair defects, including BRCA1 dysfunction, associated with TNBC, exploration of PARP1 expression in breast cancers related to expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) led to the observation that negative expression of any of the 3 receptors was associated with upregulation of PARP1 expression, compared with receptor-positive tissues. To validate these observations, an independent set of breast adenocarcinomas was evaluated and demonstrated >2-fold upregulation of PARP1 in approximately 70% of primary breast adenocarcinomas, including TNBC, compared with syngeneic nonmalignant breast tissues. Immunohistochemistry (IHC) showed that upregulation of the PARP1 gene was consistent with increased protein expression in TNBC. These analyses suggest a potential biological role for PARP1 in several distinct malignancies, including TNBC. Further investigation of PARP1 as a biomarker for the therapeutic activity of PARP inhibitor-based therapy is warranted.

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Transcriptional roles of PARP1 in cancer.

Matthew J Schiewer, Karen Knudsen (2014)

Poly (ADP-ribose) polymerase-1 (PARP1) is an abundant, ubiquitously expressed NAD(+)-dependent nuclear enzyme that has prognostic value for a multitude of human cancers. PARP1 activity serves to poly (ADP-ribose)-ylate the vast majority of known client proteins and affects a number of cellular and biologic outcomes, by mediating the DNA damage response (DDR), base-excision repair (BER), and DNA strand break (DSB) pathways. PARP1 is also critically important for the maintenance of genomic integrity, as well as chromatin dynamics and transcriptional regulation. Evidence also indicates that PARP-directed therapeutics are "synthetic lethal" in BRCA1/2-deficient model systems. Strikingly, recent studies have unearthed exciting new transcriptional-regulatory roles for PARP1, which has profound implications for human malignancies and will be reviewed herein.

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Author and article information

Contributors

Paulina Gil-Kulik:

ORCID: http://orcid.org/0000-0003-3119-981X

pgil.poczt@vp.pl

Ewa Dudzińska: ewa.dudzinska@umlub.pl

Elżbieta Radzikowska-Büchner: eradzikowska@radzikowskaclinic.pl

Joanna Wawer: jwaawer@gmail.com

Mariusz Jojczuk: mariusz.jojczuk@umlub.pl

Adam Nogalski: adam.nogalski@umlub.pl

Genowefa Anna Wawer: genowefa.wawer@umlub.pl

Marcin Feldo: marcin.feldo@umlub.pl

Wojciech Kocki: w.kocki@pollub.pl

Maria Cioch: maria.cioch@umlub.pl

Anna Bogucka-Kocka: anna.kocka@umlub.pl

Mansur Rahnama: mansur.rahnama@umlub.pl

Janusz Kocki: janusz.kocki@umlub.pl

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 18 May 2020

Publication date PMC-release: 18 May 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 435

Affiliations

[1 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Department of Clinical Genetics, , Medical University of Lublin, ; 11 Radziwillowska Str, 20-080 Lublin, Poland

[2 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Department of Public Health, Faculty of Health Sciences, , Medical University of Lublin, ; 1 Chodźki Str, 20-093 Lublin, Poland

[3 ]Department of Plastic Surgery, Saint Elizabeth’s Hospital, 1 Goszczynskiego Str, 02-616 Warsaw, Poland

[4 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Chair and Department of Trauma Surgery and Emergency Medicine, , Medical University of Lublin, ; 16 Staszica Str, 20-081 Lublin, Poland

[5 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Department of Foreign Languages Medical University of Lublin, ; 4 Jaczewskiego Str, 20-090 Lublin, Poland

[6 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Chair and Department of Vascular Surgery and Angiology, , Medical University of Lublin, ; 11 Staszica Str, 20-081 Lublin, Poland

[7 ]GRID grid.1035.7, ISNI 0000000099214842, Department of Architecture and Urban Planning, , University of Technology, ; 40 Nadbystrzycka Str, 20-618 Lublin, Poland

[8 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Chair and Department of Hematooncology and Bone Marrow Transplantation, , Medical University of Lublin, ; 11 Staszica Str, 20-081 Lublin, Poland

[9 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Chair and Department of Biology and Genetics, , Medical University of Lublin, ; 4a Chodźki Str, 20-093 Lublin, Poland

[10 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Chair and Department of Dental Surgery Medical University of Lublin, ; 7 Karmelicka Str, 20-081 Lublin, Poland

Author information

Paulina Gil-Kulik http://orcid.org/0000-0003-3119-981X

Article

Publisher ID: 6903

DOI: 10.1186/s12885-020-06903-4

PMC ID: 7236215

PubMed ID: 32423430

SO-VID: c220b13b-df58-4c85-99e3-e5b9b7e1d783

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 10 December 2019

Date accepted : 26 April 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005632, Narodowe Centrum Badań i Rozwoju;

Award ID: STRATEGMED3/303570/7/NCBR/2017

Award Recipient : Janusz Kocki

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: parp1,parp2,parp3,trpm2 gene expression,aml,hematopoietic stem cells

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: parp1, parp2, parp3, trpm2 gene expression, aml, hematopoietic stem cells

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

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Abstract

Background

Methods

Results

Conclusions

Related collections

CRISPR/Cas9 editing in human blood

Most cited references 22

Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2.

Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types.

Transcriptional roles of PARP1 in cancer.

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