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

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 anti-metabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is to reprogram gene expression in a metabolism-dependent manner. MondoA (also known as 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 a worse survival in pediatric common acute lymphoblastic leukemia (B-ALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces 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 (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced PDH 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 a 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.

Normal and Neoplastic Growth Suppression by the Extended Myc Network

“…These studies supported the idea that MondoA maintains a differentiation block in ALL blasts. Consistent with this finding, a subsequent study showed leukemic blasts with the highest levels of MondoA were associated with shorter survival [ 95 ].…”

“…They tend to encode enzymes involved in carbohydrate and lipid metabolism; mitochondrial and ribosomal proteins and factors that regulate translational initiation, elongation and termination [ 31 , 39 , 41 , 42 , 46 , 70 , 71 , 72 , 73 , 76 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Together, these findings indicate that, via selective, cytoplasmic-nuclear partitioning, sharing of Mxd1,4 and Mnt and binding to both common and unique target genes, this “Extended Myc Network” cross-talks, while simultaneously communicating with and responding to the metabolic cues and reservoirs needed to support energy-intensive processes such as translation and proliferation [ 36 , 42 , 64 , 65 , 69 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ].…”

Normal and Neoplastic Growth Suppression by The Extended Myc Network

“…These studies supported the idea that MondoA maintains a differentiation block in ALL blasts. Consistent with this finding, a subsequent study showed leukemic blasts with the highest levels of MondoA were associated with shorter survival [84].…”

“…They tend to encode enzymes involved in carbohydrate and lipid metabolism; mitochondrial and ribosomal proteins and factors that regulate translational initiation, elongation and termination [21,33,50,[57][58][59][60]63,[65][66][67][68][69][70][71][72][73][74][75][76][77][78]. Together these findings indicate that, via selective, cytoplasmic-nuclear partitioning, sharing of Mxd1,4 and Mnt and binding to both common and unique target genes, this "Extended Myc Network" cross-talks, while simultaneously communicating with and responding to the metabolic cues needed to support energy-intensive processes such as translation and proliferation [43,[50][51][52]56,[77][78][79][80][81][82][83][84][85].…”

Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress

“…The extracellular acidification rate (ECAR), a measure of glycolysis, and oxygen consumption rate (OCR) were determined using an XF96 Extracellular Flux Analyzer (Seahorse Bioscience) as described. 23 …”