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Different Regulation of PARP1, PARP2, PARP3 and TRPM2 Genes Expression in Acute Myeloid Leukemia Cells

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Different Regulation of PARP1, PARP2, PARP3 and TRPM2 Genes Expression in Acute Myeloid Leukemia Cells Gil-Kulik et al. BMC Cancer (2020) 20:435 https://doi.org/10.1186/s12885-020-06903-4 RESEARCH ARTICLE Open Access Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells Paulina Gil-Kulik1* , Ewa Dudzińska2,Elżbieta Radzikowska-Büchner3, Joanna Wawer1, Mariusz Jojczuk4, Adam Nogalski4, Genowefa Anna Wawer5, Marcin Feldo6, Wojciech Kocki7, Maria Cioch8†, Anna Bogucka-Kocka9†, Mansur Rahnama10† and Janusz Kocki1† 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. Keywords: PARP1, PARP2, PARP3, TRPM2 gene expression, AML, Hematopoietic stem cells * Correspondence: [email protected] Maria Cioch, Anna Bogucka-Kocka, Mansur Rahnama and Janusz Kocki all four authors have equal senior position in authorship 1Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str, 20-080 Lublin, Poland Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This 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. Gil-Kulik et al. BMC Cancer (2020) 20:435 Page 2 of 9 Background proven to be associated with the proliferation and sur- Acute myeloid leukemia (AML) is a heterogenic lethal vival of cells. Among TRP channels, TRPM2 is expressed disorder characterized by the accumulation of abnormal in many noncancerous cells, such as the brain and per- myeloid progenitor cells in the bone marrow which ipheral blood cells. Studies show that TRPM2 is associ- results in hematopoietic failure. A major contributing ated with various types of cancers, too [19]. factor to the high mortality rate associated with acute TRPM2 is a member of the TRP protein superfamily myeloid leukemia is developing resistance to chemother- of ion channels that can be activated by ADP-ribose, β- apy [1]. Despite various efforts in detection and treat- NAD, TNF-α, and H2O2 which results in increased ment, many patients with AML die of this cancer [1]. values of intracellular free calcium concentration ([Ca 2+ 2+_ Therefore it is important to develop novel therapeutic ]i)[20]. TRPM2 is a non-selective cationic, Ca per- options, employing strategic target genes involved in meable pore, and contains a unique C-terminal region apoptosis and tumor progression [2]. exhibiting ADP-ribose (ADPR) hydrolase activity. The Polymerases poly (ADP-ribose) PARP is a family of highest expression levels of TRPM2 are observed in the seventeen proteins that react with poly or mono ADP- cells of neuronal origin and in the myeloid lineage [21]. ribosylation, and are involved in numerous cellular pro- Data suggest that TRPM2 channels function as ‘death cesses such as DNA repair, cell death, transcription, channels’, because as a matter of fact, heterologous ex- translation, cell proliferation, or cell response to oxida- pression of TRPM2 in human embryonic kidney cells or tive stress. PARPs have the ability to modulate the tran- A172 human glioblastoma cells facilitates oxidative scriptional functions of both tumor suppressors and stress-induced cell death. Furthermore, expression of oncogenes which affects the ability of PARP to elicit TRPM2 has been demonstrated in several tumors such contextual proton and antineoplastic effects [3]. as hepatocellular carcinoma, prostate cancer, lymphoma, PARP1, PARP2, and PARP3 are involved in the repair leukemia, and lung cancer cell lines in which TRPM2 of DNA damage. Hence, it is recommended to use PARP reportedly may foster cell death [22]. TRPM2 is one ion inhibitors (PARPi) in the treatment of tumors, in par- channel that can be altered to increase apoptosis in ticular those that do not have the ability to recombine cancer cells [23]. (homologous recombination - HR) due to the mutations The aim of the study was to evaluate of PARP1, causing loss of BRCA1 or BRCA2 function. This PARP2, PARP3 and TRPM2 gene expression at mRNA phenomenon is referred to as synthetic lethality [4–6]. level in the cells of the hematopoietic system of the bone In many types of tumors, elevated PARP1 mRNA is as- marrow in patients with acute myeloid leukemia, bone sociated with poor prognosis and thus a shorter survival marrow from healthy patients, peripheral blood of time. Increased expression of PARP1 has been demon- healthy individuals, and hematopoietic stem cells from strated in various types of tumors, including breast can- the peripheral blood after mobilization. cer, soft tissue sarcomas, endometrial adenocarcinoma, gliomas, colorectal cancer, myelodysplastic syndrome, Methods neuroma, malignant lymphoma, testicular cancer, ovar- The study comprised a group of 84 patients. The study ian cancer [7–11]. PARP1 was also found in acute group consisted of 53 patients hospitalized at the myeloid leukemia and is suggested to be an independent Department and Clinic of Hematooncology with Bone prognostic factor in AML [9, 10]. Marrow Transplantation, Medical University of Lublin, Hyperactivation of PARP pathway observed in tumors Poland, among them 14 patients with acute myeloid can be used to selectively kill tumor cells. PARPi treat- leukemia - samples of bone marrow were examined, and ment was shown to be effective in monotherapy and in 39 patients in remission stage who had previously combination therapies mainly in gynecological cancers, suffered from hematologic illnesses - samples of and researchers also suspect potential of PARP inhibi- hematopoietic stem cells from the peripheral blood tors involvement in acute myeloid leukemia [9, 12, 13]. which underwent mobilization were tested, 10 patients Recent studies show that PARP may also be involved of the Chair and Clinic of Traumatic Surgery and Emer- in the epigenetic regulation maintaining stem cell pluri- gency Medicine, Medical University of Lublin. The pa- potency, and their expression is probably necessary for tients had normal bone marrow sampled during hip the proper differentiation of stem cells, including replacement surgery, and 21 healthy volunteers from hematopoietic stem cells. Some authors even suggest whom peripheral blood was collected. The study groups that PARP can be used to reprogram somatic stem cells were similar in terms of age and gender. towards induced pluripotent stem cell (iPSC) [14–18]. The material from patients with acute myeloid Transient receptor potential (TRP) channels are cation leukemia was collected at the time of diagnosis, before channels associated with cancer. To date, TRPM mem- the treatment was initiated. The AML group consisted bers including TRPM2, 4, 5, 7 and 8 have also been of 7 women and 7 men,
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