MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress

Sipol, Alexandra; Hameister, Erik; Xue, Busheng; Hofstetter, Julia; Barenboim, Maxim; Oellinger, Rupert; Jain, Gaurav; Prexler, Carolin; Rubio, Rebeca Alba; Baldauf, Michaela C.; Franchina, Davide G.; Petry, Andreas; Schmaeh, Juliane; Thiel, Uwe; Goerlach, Agnes; Cario, Gunnar; Brenner, Dirk; Richter, Guenther H. S.; Gruenewald, Thomas G. P.; Rad, Roland; Wolf, Elmar; Ruland, Juergen; Sorensen, Poul H. und Burdach, Stefan E. G. (2022): MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress. In: Blood, Bd. 139, Nr. 8: S. 1184-1197

Abstract

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 ametabolism-dependentmanner. MondoA (also known asMyc-associated factor X-like protein X-interacting protein [MLXIP]), amember of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role ofMondoA inmalignancy is not fully understood and the underlyingmechanisminmetabolic 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 thatMondoA depletion reduces the transformational capacity of B-ALL cells in vitro and dramatically inhibitsmalignant 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 tomitigatemetabolic stress upon loss ofMondoAin B-ALL. Our findings give novel insight into the function ofMondoAin pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-4971
• Sprache: Englisch