[en] Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired antimetabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is reprogramming gene expression in a metabolism-dependent manner. MondoA (also known as Myc-associated factor X-like protein X-interacting protein [MLXIP]), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets, we found that MondoA overexpression is associated with worse survival in pediatric common acute lymphoblastic leukemia (ALL; B-precursor ALL [B-ALL]). Using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and RNA-interference approaches, we observed that MondoA depletion reduces the transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced pyruvate dehydrogenase activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. Our findings give novel insight into the function of MondoA in pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored.
Disciplines :
Immunology & infectious disease
Author, co-author :
Sipol, Alexandra; Children's Cancer Research Center, Department of Pediatrics
Hameister, Erik ; Institute of Clinical Chemistry and Pathobiochemistry, Technische Universität München, Munich, Germany
Xue, Busheng ; Children's Cancer Research Center, Department of Pediatrics
Hofstetter, Julia ; Cancer Systems Biology Group, Biochemistry and Molecular Biology, Universität Würzburg, Würzburg, Germany
Barenboim, Maxim; Children's Cancer Research Center, Department of Pediatrics
Öllinger, Rupert ; Institute of Molecular Oncology and Functional Genomics, Technische Universität München, Munich, Germany
Jain, Gaurav; Institute of Molecular Oncology and Functional Genomics, Technische Universität München, Munich, Germany
Prexler, Carolin ; Children's Cancer Research Center, Department of Pediatrics
Rubio, Rebeca Alba; Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany
Baldauf, Michaela C; Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany
Franchina, Davide G ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Petry, Andreas; Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technische Universität München, Munich, Germany
Schmäh, Juliane; Department of Pediatrics, Schleswig-Holstein University Medical Center, Kiel, Germany
Thiel, Uwe; Children's Cancer Research Center, Department of Pediatrics ; Comprehensive Cancer Center (CCC) München and Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site, Munich, Germany
Görlach, Agnes; Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technische Universität München, Munich, Germany ; German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Partner Site, Munich, Germany
Cario, Gunnar; Department of Pediatrics, Schleswig-Holstein University Medical Center, Kiel, Germany
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark, and
Richter, Günther H S ; Children's Cancer Research Center, Department of Pediatrics ; Comprehensive Cancer Center (CCC) München and Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site, Munich, Germany
Grünewald, Thomas G P; Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany ; Comprehensive Cancer Center (CCC) München and Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site, Munich, Germany
Rad, Roland; Institute of Molecular Oncology and Functional Genomics, Technische Universität München, Munich, Germany ; Comprehensive Cancer Center (CCC) München and Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site, Munich, Germany
Wolf, Elmar ; Cancer Systems Biology Group, Biochemistry and Molecular Biology, Universität Würzburg, Würzburg, Germany
Ruland, Jürgen ; Institute of Clinical Chemistry and Pathobiochemistry, Technische Universität München, Munich, Germany ; Comprehensive Cancer Center (CCC) München and Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site, Munich, Germany
Sorensen, Poul H; Children's Cancer Research Center, Department of Pediatrics ; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
Burdach, Stefan E G ; Children's Cancer Research Center, Department of Pediatrics ; Comprehensive Cancer Center (CCC) München and Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site, Munich, Germany ; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
A.S. received grants from Cura Placida, the Children's Cancer Research Foundation (CP102/120815), and TRANSAID Stiftung für Krebskranke Kinder (8810001358 GCP). E.H. received a grant from the Else-Kröner-Stiftung. B.X. was supported by the Chinese Scholarship Council (CSC; no. 201908210290). The laboratory of T.G.P.G. was supported by grants from German Cancer Aid (DKH-70112257), the Gert and Susanna Mayer Foundation, and the Barbara and Wilfried Mohr Foundation. M.B. was supported by Doris Stiftung. S.E.G.B. and U.T. were supported by Willhelm Sander Stiftung und Cura Placida. D.B. was funded by the ATTRACT program (A14/BM/7632103), and a CORE grant (C18/BM/12691266) of the Luxembourg National Research Fund (FNR). EW was funded by European Research Council (TarMYC to) and German Research Foundation (DFG;WO 2108/1-1).The authors thank Daniel P. Kelly (Cardiovascular Institute and Institute for Diabetes, Obesity and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA) and Rick B. Vega (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL) for providing SBI477. The authors also thank Torsten Haferlach (Munich Leukemia Laboratory [MLL]) for provision of annotated leukemia gene-expression data. The experimental support by Oxana Schmidt is gratefully acknowledged, as well as the graphical abstract art work by Ljuba Sipol. The authors also thank the following clinicians for providing samples used in this work: Katja Gall, Angela Wawer, and Irene Teichert-von Lüttichau. The authors appreciate the technical assistance provided by Nadine Kliese during the submission process. A.S. received grants from Cura Placida, the Children's Cancer Research Foundation (CP102/120815), and TRANSAID Stiftung für Krebskranke Kinder (8810001358 GCP). E.H. received a grant from the Else-Kröner-Stiftung. B.X. was supported by the Chinese Scholarship Council (CSC; no. 201908210290). The laboratory of T.G.P.G. was supported by grants from German Cancer Aid (DKH-70112257), the Gert and Susanna Mayer Foundation, and the Barbara and Wilfried Mohr Foundation. M.B. was supported by Doris Stiftung. S.E.G.B. and U.T. were supported by Willhelm Sander Stiftung und Cura Placida. D.B. was funded by the ATTRACT program (A14/BM/7632103), and a CORE grant (C18/BM/12691266) of the Luxembourg National Research Fund (FNR). EW was funded by European Research Council (TarMYC to) and German Research Foundation (DFG;WO 2108/1-1).
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