Abstract 1421: Overexpression of the pro-glycolytic transcription factor MondoA enhances malignant potential of ALL in vivo
Authors: Sipol Alexandra A. , Richter Günther H.S. , Wernicke Caroline M. , Grunewald Thomas G.P. , Burdach Stefan 
Published: May 2015

Introduction. Most cancer cells use glycolysis for energy production regardless of whether they are under normoxic or hypoxic condition (Koppenol et al., 2011). Warburg described this metabolic hallmark of cancer cells, named aerobic glycolysis. The high dependence of tumor cells on glucose utilization may be exploited for therapeutic intervention. One of the genes, which have effects on glucose metabolism, is MondoA. It is a transcription factor (Stoltzman et al., 2008) highly over-expressed in ALL (Wernicke et al. 2012). MondoA:MLX heterodimers have been discussed as a parallel network to MYC:MAX, which have broad effects on cellular growth, proliferation and survival (Kaadige et al., 2010; Sloan and Ayer, 2010). Knockdown experiments revealed that MondoA impacts on metabolic activity of leukemic cells and their glucose utilization. Furthermore MondoA knockdown resulted in a more differentiated leukemic phenotype and shifted gene expression towards a signature favoring apoptosis and thus reducing the signs of aggressiveness of leukemia cells in vitro (Wernicke et al. 2012). Based on our previous work, we hypothesized that assessing survival of leukemia bearing mice may reveal the role of MondoA in ALL in vivo.

Methods. The murine/human xeno-transplantation model of leukemia was used (Richter et al. 2009). NALM-6 ALL cell lines were transduced by retroviral gene transfer of constructs, harboring specific for MondoA short hairpin RNA (shRNA), and injected into immune deficient Rag2-/-γC-/- mice. The tumor burden were measured and compared to the one in control mice bearing leukemia cells transduced with nonfunctional siRNA. Tumor burden of mice were evaluated by cyto- and histochemistry and by measuring the CD10+ blast cells content in blood, spleen and bone marrow by flow cytometry.

Results. These experiments showed that MondoA knockdown significantly reduced leukemia cells' proliferation in mice as compared to control group. Although signs of leukemia engraftment were observed in all mice, the differences in amount of CD10+ blasts cells in blood, bone marrow and spleens in the controls and in the MondoA knockdown group were significant (p= 0,0079). Experimental results also showed a decrease of the leukemic infiltration-induced swelling of the spleen in the group with MondoA knockdown. Median spleen weight was 0.22g and 0.08g in the control and in the experimental group.

Conclusion. These findings demonstrate that the downregulation of MondoA by RNA interference significantly delays leukemic burden and malignancy of B cell ALL in vivo and further confirm that MondoA is an attractive target for targeted and immune therapy of ALL.

Citation Format: Alexandra A. Sipol, Günther H.S. Richter, Caroline M. Wernicke, Thomas G.P. Grunewald, Stefan Burdach. Overexpression of the pro-glycolytic transcription factor MondoA enhances malignant potential of ALL in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1421. doi:10.1158/1538-7445.AM2014-1421