MondoA mediates in vivo aggressiveness of common ALL by induction of HIF1a

• Published in: European journal of cancer (1990) Vol. 69; p. S50
• Main Authors: Sipol, A, Grunewald, TGP, Schmaeh, J, Den Boer, ML, Rubío, R Alba, Baldauf, M, Wernicke, C, Horstmann, M, Cario, G, Richter, G, Burdach, S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science Ltd 01-12-2016
• Subjects: Acute lymphoblastic leukemia; Acute myeloid leukemia; Birth weight; Blood; Bone marrow; Cancer; Cellular stress response; Children; Correlation; DNA microarrays; Gastrointestinal cancer; Gene expression; Glycolysis; Hypoxia; Immunodeficiency; Leukemia; Leukemogenesis; Lymph nodes; Lymphatic leukemia; Lymphocytes; Lymphocytes B; Malignancy; Metabolites; Mice; Oxidative phosphorylation; Peripheral blood; Phosphorylation; Proteins; Ribonucleic acid; Risk; RNA; Spleen; Stress response; Transcription factors; Tumors; Xenografts; Xenotransplantation
• ISSN: 0959-8049; 1879-0852

Leukemia incidence in childhood correlates with birth weight (Burdach et al. 1999) and drivers of metabolic reprogramming in cancer provide targets for therapy. 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 by increased glycolysis. Leukemic counterparts of B lymphocytes exploit these features for their survival. Glucose-derived metabolites control the nuclear activity of the transcription factors MondoA, a factor critical for longevity in cenorhabdis. Here we report on the expression of MondoA in common acute lymphoblastic leukemia (cALL) compared to other malignancies, its role in malignancy of cALL in vivo, downstream pathways and correlation with relapse risk. Our human/murine xenotransplantation model with immunodeficient RAG2gc mice was used (Richter et al. 2009). NALM6 and 697 cALL lines were lentivirally transduced with MondoA short hairpin RNA (shRNA). Upon successful MondoA knock down (KD), KD and control lines were injected into the mice; CD1O+ blasts in blood, spleen and marrow were assessed. We found MondoA to be most strongly expressed in pediatric cALL and AML. Moreover MondoA expression was high in gastrointestinal stromal tumors and alveolar rabdomyosarcoma. 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 treated mice after MondoA KD. Further microarray analysis revealed an induction of aerobic glycolysis switch genes and hypoxia- response by MondoA. Moreover, HIF1a stabilization required MondoA expression and MondoA protein is induced under hypoxia. 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 F-fIFTh.