Targeting mitochondrial transcription in acute myeloid leukemia

Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy which arises from accumulation of immature myeloid cells in the bone marrow (BM). The present research approaches for finding new therapies of AML are much focused on targeting the different genetic alterations seen in AML but many of them fail, probably due to the heterogeneity of the leukemic cells to be targeted. Altered energy and metabolic dependency in a majority of cancers has been the focus of several studies. However, little is known about targeting these properties in AML. The dependence of these basic physiological properties, notably, cellular metabolism is expected to be the same, irrespective of the genetic rearrangements of the cells. Mitochondria as important cell organelles are responsible for cellular energy levels, metabolism and apoptosis. Recently, mitochondrial dependency has been shown to play an important role in the progression of AML. AML cells exhibit high expression of mitochondrial RNA polymerase (POLRMT) which indirectly leads to high oxidative phosphorylation. Based on its upregulation as well as unique phage-originated structure, POLRMT would have a great potential as a therapeutic target in AML. In order to investigate the effect of inhibiting POLRMT, we have generated leukemia cell culture models by expressing the fusion protein MLL-AF9 or its downstream collaborators Hoxa9 and Meis1 in murine bone marrow cells. These cells gain proliferation advantage, are transplantable and induce rapid leukemia in wildtype mice. A broad spectrum of different human leukemia cell lines was also investigated. Murine leukemic BM cells as well as human leukemia cell lines were treated with 2-C-Methyladenosine (2-CM) a nucleoside analogue which inhibits mitochondrial POLRMT. We could see a significant decline in proliferation in both human cell lines and in murine leukemic cells in a concentration-dependent manner, measured by the MTT assay. Next we have started to investigate the effect of 2-CM in vivo in our BM transplantation mouse model. The drug has been administrated for eleven days two weeks post transplantation and compared with mice treated with only the vehicle. The drug has been well tolerated by the mice and is now being followed to determine whether the drug can delay or prevent onset of acute leukemia. In conclusion, our in vitro experiment show promising results suggest that inhibiting the mitochondrial transcription can be used as a potential therapeutic strategy in the treatment of AML but our in vivo results are still pending but will be presented.