Observed by us 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 stem cells suggest that in physiological state there is mutual positive regulation of PARPs and TRPM2 genes expression. In the bone marrow cells of the patients with acute myelogenous leukemia, significant correlations were not observed between the expression of the examined genes. Our research suggests that there is a different regulation of PARP1, PARP2, PARP3, and TRPM2 genes expression in acute myelogenous leukemia cells.
Interestingly, the bone marrow cells of patients with acute myelogenous leukemia show over expression 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. Our studies may suggest disrupted signaling between TRPM2 and PARP genes in cancer cells. In addition, the determined correlation between reduced TRPM2 gene expression and decreased PARP1 gene expression and shorter overall survival time indicates the prognostic significance of the expression of these genes in AML.
Similarly, the study by Zeng et al.  showed that knocking down TRPM2 increased PARP activity in prostate cancer cells through a unresolved mechanism . In recent years, scientists have devoted much attention to the role of TRP channels in cancer. Among other things, it has been shown that TRPM2 is involved in cell migration and cell death, which are the key processes of cancer cell death . The results of the studies by Zeng et al.  showed that in non-cancerous cells, TRPM2 proteins are mainly located at the plasma membrane where they mediate sodium and calcium influx on oxidative stimulation. Cation influxes may lead to membrane depolarization and changes in calcium homeostasis that can lead to programed cell death. In cancer cells, the role of TRPM2 as a plasma membrane ion channel is less important because of the internalization and nuclear localization of TRPM2. Numerous TRPM2 proteins are translocated into the nucleus where they may have an important enzymatic function related to cancer cell proliferation .
The cited studies also confirm our analyses in which we showed that in tumor cells TRPM2 gene expression is significantly decreased whereas PARP1 and PARP2 expression is significantly increased, which may indicate that TRPM2 gene loses its function in tumor cells. In addition, we have shown that in the physiological state there is a positive relationship between PARP1, PARP2, and TRPM2, which is disturbed in cancer cells.
Correct regulation between the examined genes is extremely unimportant in the context of cell functioning, and its dysregulation may block apoptotic cell death, affect the progression of the cell cycle and increase cell proliferation as well as increase the possibility of DNA repair by overexpressing PARP. On the one hand, the activity of polymerase poli(ADP-ribose) depends on the intracellular calcium concentration, on the other hand polymers of (ADP-ribose) synthesized by PARP1, PARP2 and PARP3 stimulate TRPM2 in the normal cells .
The researchers observed that the expression of TRPM2 in AML subgroups is the higher the more differentiated AML cells are . Klumpp et al. demonstrated that TRPM2 plays a key role in response to DNA damage in leukemic T lymphocytes. The researchers argue that irradiated Jurkat cells use TRPM2 channels to control cell cycle arrest in the G2/M phase . Sumoza-Toledo et al. have demonstrated that the low TRPM2 expression may be used to predict adverse prognosis in ER-HER + breast cancer. According to the researchers, TRPM2 is a promising biomarker of aggressiveness for breast cancer, and a potential target for new therapies . TRPM2 channel has been identified as playing an important role in several types of cancers  including breast cancer, neuroblastoma, prostate cancer, head and neck cancer, melanoma , and colorectal cancer [31,32,33]. Potential TRPM2 involvement was confirmed in cell proliferation, facilitation of cell survival, prostate cancer, melanoma, genomic stability of breast cancer cells, promotion, survival and metastases in the head and neck . The researchers observed that after TRPM2 silencing, the level of DNA damage in breast cancer cells was significantly increased, which was not observed in non-cancer breast cells after similar therapy . So we speculate that therapy directed simultaneously at TRPM2 and PARPs would cause the cancer cells death as a result of damage accumulation and the inability to DNA repair.
Many studies indicate that TRPM2 is an ion channel that is modulated, and that can be altered to increase apoptosis in cancer cells including acute leukemia cells. Yanamandra et al.  identified molecular mechanisms by which tipifarnib produces cell death in AML and multiple myeloma cell lines (U937 and 8226 respectively). Several plasma membrane calcium channels have been identified in U937 cells that may potentially account for the elevated [Ca2+]I, and concomitant cell death in response to tipifarnib application reported by Yanamandra. They include TRPM2, TRPM7, and store-operated calcium channels. In U937 cells, the activation of TRPM2 with either H2O2 or tumor necrosis factor-α increased cleavage of caspase-8, caspase-9, caspase-3, caspase-7, PARP, and consequently cell death was enhanced in a [Ca2+] . Based on the conducted studies, we noted that the bone marrow and blood cell samples of the patients with acute leukemia showed statistically significantly lower mean TRPM2 gene expression compared to the normal bone marrow. Reduced expression of TRPM2 gene may be associated with disordered apoptotic cycle in cancerous cells.
Our results of TRPM2 gene expression presented the context of survival time of AML patients showed a statistically significant correlation: the higher TRPM2 gene expression in bone marrow cells at the time of diagnosis, the longer the mean survival time of the patients. A statistically significantly higher level of TRPM2 gene expression was observed in the patients whose survival was longer than 5 years, compared to the patients whose survival was less than 5 years. The presented results suggest that the expression of TRPM2 gene in the marrow cells of AML patients is a possible prognostic marker.
Our results show also increased expression of PARP1 and PARP2 gene in AML cells. In many studies PARP1 expression was found to be significantly increased in several malignant tissues, e.g. breast, uterine, lung, ovarian. Within breast infiltrating ductal carcinoma samples tested, mean PARP1 expression was significantly higher compared to normal breast tissue .
The latest data also confirm that PARP1 was highly expressed in cytogenetically normal AML patients and AML cell lines compared to normal bone marrow cells. It may indicate that PARP1 plays a critical role in the development of AML . Research by Fonfria et al.  confirms the hypothesis that PARP enzyme activity is a central component of the pathway linking oxidative stress with TRPM2 activation . Intracellular Ca2+ regulation has a crucial role in tumorigenesis, including cell replication and apoptosis. Nuclear expression of TRPM2 may also influence nuclear Ca2+ concentration .
In our studies we showed that in the bone marrow cells of patients with acute myeloid leukemia, PARP1 and PARP2 genes are overexpressed and TRPM2 gene is down-regulated, which may suggest disturbed signaling between these genes. The modified TRPM2 function may suggest disturbed signaling between TRPM2 and PARPs at the transcript level, which increases the expression of polymerases. Numerous studies have reported that overexpression of PARP genes in turn is associated with uncontrolled cell proliferation, increased DNA repair ability, and increased telomerase activity which is associated with cell immortalization .
The demonstrated in our study positive correlations between PARP1, PARP2, PARP3, and TRPM2 gene expression in the group of PBMC and in the group of BM cells suggest that in the physiological state there is mutual positive regulation of PARP family members and TRPM2 gene expression. In the bone marrow cells from the patients with acute myelogenous leukemia, significant relationships between the expression of the test genes were not observed. Our research suggests that there is a different regulation of PARP1, PARP2, PARP3, and TRPM2 gene expression in acute myelogenous leukemia cells. We speculate that correct signaling between TRPM2 and PARPs is essential for physiology, and its loss may affect the development of acute leukemia. Regulation of PARP1, PARP2, PARP3, and TRPM2 genes expression may provide a new therapeutic strategy against AML.
Moreover, our studies have shown that there is a negative correlation between PARP1 gene expression and overall survival in the group of cells from the marrow of AML patients. It has been shown that the higher PARP1 expression at the mRNA level, the shorter the patients' survival. In the group of patients whose survival was over 5 years, PARP1 expression was statistically significantly lower in comparison with patients whose overall survival was less than 5 years, which confirms the prognostic significance of PARP1.