Mondoa Promotes Resistance to Asparaginase Treatment in B-ALL By Inducing Asparagine Synthesis
Bibliographic record
Abstract
Background: Cancer cells often exhibit rapid proliferation and uncontrolled division, employing adaptations to metabolic stress to maintain homeostasis and survival. MondoA (Myc-associated factor X-like protein X-interacting protein [MLXIP]), a member of the MYC interactome, is a metabolic sensor playing an important role in cancer cell adaption to stress. Our previous work demonstrated that increased MondoA expression correlates with poor outcomes in subgroups of pediatric common acute lymphoblastic leukemia (ALL; B-precursor ALL [B-ALL]) by inducing resistance to metabolic stress (Sipol et al. BLOOD 2022). Methods: We explored the role of MondoA in resistance to L-Asparaginase (ASNase) treatment, a major non-genotoxic therapeutic principle in pediatric B-ALL, which depletes Asparagine (Asn) in the bloodstream. Utilizing CRISPR/Cas9 technology, we generated MondoA knock-out B-ALL NALM6 cell line (MKO) to study the effects on cellular metabolism and resistance mechanisms. We tested the effect of ASNase on cell viability and performed multi-omics analyses to evaluate changes in metabolic pathways and MYC binding sites in both MKO and control cells. Results: Our study demonstrates that MondoA induces resistance to ASNase treatment in B-ALL cell lines. In our experiments, MKO cells exhibited a 92% loss of viability upon ASNase treatment, compared to an 84% loss in control cells (N = 4). Mechanistically, MondoA knock-out resulted in a redistribution of MYC binding to promoter regions, significantly affecting the epigenome, transcriptome, and proteome of the cells. Proteomic analysis revealed reduced expression of electron transport chain (ETC) complexes and key tricarboxylic acid (TCA) cycle enzymes, resulting in lower aspartate (Asp) production, a substrate for Asparagine Synthetase (ASNS). Alpha-ketoglutarate supplementation rescued MKO cells, likely by enhancing Asp production through the TCA cycle; this effect was not observed in control cells. Additionally, we discovered that ASNase resistance partially depends on sufficient glutamine (Gln) levels, another substrate for Asn de novo synthesis. Multi-omics coherence analysis of ASNS-promoter MYC binding, transcriptome, and proteome revealed downregulation of ASNS in MKO cells. These data are supported by our previous transcriptome analysis results of MondoA knock-down in other B-ALL cell lines, Reh and 697, which showed downregulation of ASNS transcripts upon silencing MondoA expression. Conclusion: Our findings suggest a pivotal role of MondoA in ASNase therapy-resistant B-ALL and highlight its potential as a therapeutic target to improve treatment outcomes in pediatric B-ALL by enhancing sensitivity to ASNase asparaginase therapy. Key words: B-ALL, MondoA, L-Asparaginase resistance.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".