Transient potential receptor melastatin-2 (Trpm2) does not influence murine MLL-AF9-driven AML leukemogenesis or in vitro response to chemotherapy

Abstract

Transient potential receptor melastatin-2 (TRPM2) is a non-selective cationic, Ca2+ permeable transmembrane pore that is preferentially expressed in cells of the myeloid lineage, and modulates signaling pathways converging onto NF-kB. This is of potential interest for AML therapy, as NF-κB signaling is emerging as a key pathway mediating drug resistance and leukemia initiating cell survival in AML, and inhibition of NF-κB signaling has been shown to be synergistic with chemotherapy. TRPM2 is overexpressed in AML compared to normal bone marrow, with highest levels in the FAB M3-6 subtypes. To determine the effect of loss of Trpm2 in a defined genetic model, we established MLL-AF9 driven AML on a Trpm2−/− genetic background. Trpm2−/− MLL-AF9 leukemias displayed reduced NF-κB phosphorylation and nuclear translocation. In vivo primary and secondary recipients of Trpm2−/− MLL-AF9 leukemias showed increased latency compared to recipients of wild type leukemia cells. However, the difference in latency was small, and lost in tertiary transplants. The effect of loss of Trpm2 in a BCR-ABL/NUP98-HOXA9 fusion model was even smaller. Given reports that loss or inhibition of TRPM2 enhanced killing by DNA damaging agents in neuroblastoma, breast and prostate cancer cell lines, we exposed Trpm2−/− and Trpm2wt primary MLL-AF9 leukemias to doxorubicin, cytarabine and etoposide, but found no difference in IC50. The in vitro response to decitabine was also unaffected. In summary, TRPM2 does not seem to play a major role in myeloid leukemogenesis. In addition, loss of TRPM2 does not augment the cytotoxicity of standard AML chemotherapeutic agents.

Transient receptor potential ion channel TRPM2 promotes AML proliferation and survival through modulation of mitochondrial function, ROS, and autophagy

“…This is consistent with reports in neuroblastoma 31 , T-cell ALL 40 , and gastric cancer 38 in which TRPM2 depletion reduced malignant cell survival. It differs from a report examining AML generated on a Trpm2-/-genetic background in murine hematopoietic cells induced by retroviral introduction of MLL-AF9 or BCR-ABL-GFP and NUP98-HOXA9-YFP 41 . Loss of TRPM2 in that model had no major effect on leukemogenesis or potentiation of cytotoxic therapy.…”

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

“…The researchers observed that the expression of TRPM2 in AML subgroups is the higher the more differentiated AML cells are [21]. Klumpp et al demonstrated that TRPM2 plays a key role in response to DNA damage in leukemic T lymphocytes.…”

“…TRPM2 is a non-selective cationic, Ca 2 + _ permeable pore, and contains a unique C-terminal region exhibiting ADP-ribose (ADPR) hydrolase activity. The highest expression levels of TRPM2 are observed in the cells of neuronal origin and in the myeloid lineage [21].…”

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

“…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 [28]. The results of the studies by Zeng et al [20] showed that in non-cancerous cells, TRPM2 proteins are mainly located at the plasma membrane where they mediate sodium and calcium influx on The researchers observed that the expression of TRPM2 in AML subgroups is the higher the more differentiated AML cells are [21]. Klumpp 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.…”