Abstract 4515: Metabolic stress sensor MondoA mediates <i>in vivo</i> aggressiveness of common ALL by induction of HIF1α
Authors: Alexandra A. Sipol, Thomas G. Grunewald, Juliane Schmaeh, Monique L. den Boer, Rebeca Alba Rubío, Michaela Baldauf, Caroline Wernicke, Martin Horstmann, Gunnar Cario, Günther Richter, Stefan Burdach
Journal: Cancer Research (2017)

Abstract Tumor cells evolve adaptive mechanisms to survive hypoxia, nutrient deprivation, oxidative or genotoxic stress to ultimately drive tumor progression (Sorensen et al. 2015). We previously described MondoA (also known as MLXIP, MAX like protein X interacting protein) as a metabolic stress sensor, required for leukemogenesis. Lymphocytes, in particular B Lymphocytes are adapted to hypoxic environments from their very beginning. They are destined to travel from the hypoxic bone marrow via normoxic peripheral blood to hypoxic lymph nodes. They thus are specialized in glycolysis to compensate the lack of oxidative phosphorylation under hypoxic conditions. Leukemic counterparts of B-lymphocytes exploit these features for their survival. Glucose-derived metabolites control the nuclear activity of the transcription factor MondoA. Here we report on the expression of MondoA in common B-cell acute lymphoblastic leukemia (cALL) compared to other malignancies, its role in malignancy of cALL in vivo, downstream pathways and correlation with relapse risk. Methods. Our human/murine xenotransplantation model with immunodeficient RAG2-/-gc-/- mice was used (Richter et al. 2009). NALM6 and 697 cALL lines were lentivirally transduced with MondoA short hairpin RNA. Upon successful MondoA knock down (KD), KD and control lines were injected into the mice; CD10+ blasts in blood, spleen and marrow were assessed. Results. We found MondoA to be most strongly expressed in pediatric cALL and AML. Moreover MondoA expression was high in gastrointestinal stromal tumors and alveolar rhabdomyosarcoma. MondoA KD in cALL cell lines and their subsequent analysis in xenograft mice resulted in a reduced number of leukemic blasts in blood, marrow and spleen. Spleen size and weight normalized in mice after MondoA KD. Further microarray analysis revealed an enrichment of glycolytic and hypoxia response gene sets by MondoA. Moreover, HIF1a induction under hypoxia required MondoA. We demonstrate that hypoxia facilitates vincristine resistance of cALL. MondoA is induced under hypoxia and confers cALL cells chemotherapeutic resistance. Tied to these results, MondoA overexpression correlated with relapse risk; its expression was 63% higher in the very high-risk group as compared to the non-high-risk group of cALL. In conclusion, our findings demonstrate that MondoA maintains leukemic burden and aggressiveness of cALL in vivo possibly by modulating metabolic and hypoxia stress response, in particular by induction of HIF1a. Citation Format: Alexandra A. Sipol, Thomas G. Grunewald, Juliane Schmaeh, Monique L. den Boer, Rebeca Alba Rubío, Michaela Baldauf, Caroline Wernicke, Martin Horstmann, Gunnar Cario, Günther Richter, Stefan Burdach. Metabolic stress sensor MondoA mediates in vivo aggressiveness of common ALL by induction of HIF1α [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4515. doi:10.1158/1538-7445.AM2017-4515