Translocation Tales: Unraveling the MYC Deregulation in Burkitt Lymphoma for Innovative Therapeutic Strategies
Abstract
:1. Introduction
2. Epidemiology and Challenges in Treatment Approach
Region/Country | Burkitt Lymphoma Incidence |
---|---|
Asia | |
Israel | 3.77 |
Saudi Arabia | 2.41 |
Turkey | 2.30 |
Republic of Korea | 1.72 |
Japan | 1.55 |
Jordan | 1.17 |
Thailand | 0.88 |
India | 0.59 |
China | 0.45 |
Europe | |
Estonia | 5.67 |
Switzerland | 4.12 |
Belgium | 3.72 |
Norway | 3.49 |
Spain | 3.34 |
Italy | 3.23 |
The Netherlands | 3.16 |
France | 3.13 |
Lithuania | 3.00 |
Denmark | 2.92 |
United Kingdom | 2.68 |
Ireland | 2.64 |
Austria | 2.44 |
Germany | 2.43 |
Czech Republic | 1.97 |
Belarus | 1.96 |
Ukraine | 1.52 |
Poland | 0.88 |
Russian Federation | 0.72 |
Oceania | |
New Zealand | 3.21 |
Australia | 3.12 |
Africa | |
Malawi | 19.3 |
Uganda | 4.8 |
Zambia | 4.2 |
Rwanda | 3.5 |
Burundi | 3.4 |
South Sudan | 2.5 |
Tanzania | 2.2 |
Madagascar | 2.1 |
Kenya | 1.7 |
Mozambique | 1.7 |
Ethiopia | 0.4 |
Cameroon | 8.0 |
Congo, Democratic People Republic of | 2.9 |
Angola | 2.1 |
Chad | 1.7 |
Sudan | 2.0 |
Egypt | 1.7 |
Morocco | 1.7 |
Algeria | 0.9 |
South Africa | 1.6 |
Cote d’Ivoire | 4.6 |
Nigeria | 2.8 |
Ghana | 2.4 |
Senegal | 2.4 |
Burkina Faso | 2.2 |
Mali | 1.4 |
Niger | 1.2 |
Central/South America | |
Puerto Rico | 5.32 |
Colombia | 5.10 |
North America | |
US white people | 4.94 |
United States (overall) | 4.75 |
US black people | 4.04 |
Canada | 2.35 |
3. MYC Deregulation in Burkitt Lymphoma: Mechanisms and Implications
- (1)
- Chromosomal Translocations: In Burkitt lymphoma (BL), the most common mechanism of MYC deregulation involves chromosomal translocations that place the MYC gene under the control of immunoglobulin (Ig) enhancer elements, leading to constitutive activation of MYC expression in B-cells [34,35,36,37]. The translocation t(8;14)(q24;q32), found in approximately 80% of BL cases, is the most frequent MYC translocation in this disease [38,39]. Additional MYC translocations in BL include t(2;8)(p12;q24) and t(8;22)(q24;q11) [39,40,41]. Constitutive MYC overexpression drives uncontrolled cell proliferation, a defining feature of BL.
- (2)
- Point Mutations: In addition to chromosomal translocations, point mutations in MYC have been identified in BL. The T58A mutation increases MYC protein stability by inhibiting its degradation via the ubiquitin–proteasome pathway and enhances MYC transcriptional activity by increasing its association with transcriptional co-activators, such as TRRAP and p300/CBP [42,43].
- (3)
- Genomic Instability: MYC translocation also contributes to the genomic instability of BL cells. MYC-induced DNA replication stress can cause DNA double-strand breaks, leading to chromosomal rearrangements and mutations [44,45]. This instability can contribute to the clonal evolution of BL and the acquisition of additional mutations that drive tumor progression and resistance to therapy [46].
- (4)
- Signaling Pathways: The molecular mechanisms of MYC-induced transformation in BL are complex and involve the deregulation of multiple signaling pathways. MYC regulates the expression of genes involved in several growth/proliferation regulating signaling pathways, including the Wnt/β-catenin, NF-κB, and PI3K/Akt/mTOR pathways [47,48]. Deregulation of these pathways can contribute to the aggressive behavior of BL and resistance to therapy.
- (5)
- MYC and Cancer Metabolism: MYC has been implicated in cancer metabolism, particularly the Warburg effect, where it promotes glucose metabolism and aerobic glycolysis in cancer cells [49,50]. This metabolic adaptation enables cancer cells to withstand nutrient scarcity and hypoxic environments. MYC also plays a role in mitochondrial biogenesis and regulation in response to growth signals and cell cycle progression [51,52,53]. This provides an opportunity for therapeutic targeting of mitochondrial factors regulated by MYC in the context of the Warburg effect in cancer.
- (6)
- MYC and Immune Regulation: Studies on human patient samples and transgenic mouse models have provided evidence that MYC is involved in the regulation of innate immune regulator CD-47 and the well-known adaptive immune checkpoint PD-L1 [54,55,56]. Saravia et. al [57] found that MYC also promotes the differentiation and activation of regulatory T-cells, which suppress immune responses and promote tumor growth. MYC influences the expression of genes involved in T-cell activation while suppressing the expression of genes involved in T-cell differentiation and function [57].
3.1. Mechanism of MYC Translocation and Its Significance in Accumulating Mutations on the Translocated Allele
3.1.1. Mechanism of IgH-MYC Translocation
3.1.2. Risk Factors for Burkitt Lymphoma and IgH-MYC Translocation
- Infection with the Epstein–Barr virus (EBV): Most people are infected with EBV at some point in their lives, but in rare cases, it can increase the risk of Burkitt lymphoma. It is believed that the virus may contribute to the occurrence of the IgH-MYC translocation [62].
- Malaria: In endemic regions (such as sub-Saharan Africa), chronic malaria infection weakens the immune system and is thought to contribute to the higher incidence of Burkitt lymphoma [63].
- Immune suppression: Individuals with weakened immune systems (such as those with HIV/AIDS or organ transplant recipients) have an increased risk [64].
3.1.3. Mutations Accumulate in the Translocated MYC Allele
3.2. Additional Genetic Alterations in Burkitt Lymphoma
3.2.1. TP53 Mutations and Its Prognostic Importance in BL
3.2.2. TCF3 and ID3 Mutations in BL
3.2.3. MYC Translocation and 11q Alterations
3.3. Evolutionary Growth Advantage as an Implication of MYC Translocation in Cancer
4. Challenges in Developing Successful Therapies against MYC-Deregulated Burkitt Lymphoma
- (1)
- Heterogeneity of MYC-deregulated BL: BL tumors display significant heterogeneity, both at the genetic and epigenetic levels, which contributes to variations in treatment response [66]. This diversity requires the development of therapies that can effectively target the range of molecular alterations in MYC-deregulated BL.
- (2)
- Tumor microenvironment: The tumor microenvironment, consisting of non-cancerous cells and extracellular matrix components, can influence tumor growth and therapy resistance in BL. The interplay between tumor cells and the microenvironment may contribute to the challenges in developing effective treatments against MYC-deregulated BL [102].
- (3)
- Off-target effects: MYC plays a crucial role in normal cell function, and its inhibition may lead to undesirable off-target effects that can cause cytotoxicity in normal cells. This further complicates the development of targeted therapies against MYC [103].
- (4)
- Complexity of MYC’s roles in cellular processes: MYC is a transcription factor that regulates a myriad of cellular processes, including cell cycle progression, metabolism, and protein synthesis [66]. This multifaceted role makes it difficult to selectively target MYC without disrupting normal cellular functions.
- (5)
- Paradoxical roles of MYC: A significantly high level of MYC can induce apoptosis or programmed cell death, as a protective mechanism against uncontrolled proliferation. This phenomenon, known as “MYC-induced apoptosis”, has been well-documented in scientific literature. For example, in a study by Evan et al. [104] it was observed that overexpression of MYC leads to both cell proliferation and apoptosis. This seemingly paradoxical effect is due to the fact that while MYC drives cell cycle progression, it also sensitizes cells to a variety of apoptotic signals. Therefore, unless a second mutation occurs that inhibits apoptosis, excess MYC can lead to cell death [104].
- (6)
- MYC’s “undruggable” nature: MYC has been considered an “undruggable” target due to the lack of well-defined small-molecule binding pockets and its intrinsically disordered structure, which hampers the development of small-molecule inhibitors [20].
- (7)
- The development of resistance: Targeted therapies often face the challenge of acquired resistance, which may emerge through the activation of alternative signaling pathways or the selection of resistant clones [105].
5. Potential Strategies to Overcome Challenges
- (1)
- Patient stratification and precision medicine: An enhanced approach to patient stratification could significantly improve therapeutic efficacy in MYC-deregulated Burkitt lymphoma. Stratification informed by molecular profiling, geographical variations (e.g., HIC vs. SSA regions), and age-related criteria can identify patient subgroups likely to benefit from targeted therapies. This holistic approach could optimize personalized treatment strategies, and help in mitigating the impact of tumor heterogeneity [106].
- (2)
- Targeting the tumor microenvironment: Therapeutic strategies that modulate the tumor microenvironment can potentially enhance the effectiveness of MYC-targeted therapies. For example, immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy, can be combined with MYC-targeted treatments to improve antitumor immune responses [107].
- (3)
- Development of selective MYC inhibitors: The development of selective MYC inhibitors with reduced off-target effects can help in minimizing cytotoxicity in normal cells. Recent advancements in drug discovery technologies, such as structure-based drug design and high-throughput screening, can aid in identifying these selective inhibitors [108].
- (4)
- Indirect targeting of MYC: One approach to overcome MYC’s “undruggable” nature is to indirectly target it by modulating its transcription, translation, or protein stability [109]. Small molecules that inhibit MYC-MAX dimerization or target upstream signaling pathways regulating MYC have shown promise in preclinical studies [8].
- (5)
- Combination therapy: Combining targeted therapies against MYC with other treatment modalities, such as chemotherapy or immunotherapy, can potentially improve treatment outcomes and overcome resistance mechanisms [107].
6. Implications for Treatment
6.1. Background
6.2. Strategies for Targeting MYC in Burkitt Lymphoma
6.2.1. Small-Molecule Inhibitors and Targeted Therapies
6.2.2. Targeting MYC Deregulation via Cellular Pathways
- CDK9: CDK9, a component of the positive transcription elongation factor b (P-TEFb) complex, is necessary for transcriptional elongation by RNA polymerase II and is one of the prospective therapeutic targets. MYC-positive BL cells were found to be highly sensitive to CDK9 inhibition, leading to decreased cell viability and increased apoptosis [115].
- MCL-1 Inhibition: Inhibition of MCL-1, an anti-apoptotic protein that is often overexpressed in cancer cells, was found to be another potential therapeutic target for MYC-positive BL [116].
- AKT Pathway: MYC translocation activates the AKT pathway, which plays a crucial role in regulating cell survival, metabolism, and proliferation. Targeting the AKT pathway was suggested as a promising therapeutic approach for MYC-positive BL [117]. The combination of an AKT inhibitor and an mTOR inhibitor can synergistically induce apoptosis in MYC-driven lymphoma cells [117].
- Restoration of Wild-Type p53 Expression: Restoring wild-type p53 expression can inhibit their proliferation and induce apoptosis [77].
- Cell Proliferation and Survival Genes: Genes, such as CDK6, CCND2, and BCL2 could serve as potential therapeutic targets for MYC-positive BL [118]. Venetoclax, a BCL2 inhibitor, was found to be efficient in inducing apoptosis in MYC-positive lymphoma cells.
- XIAP Targeting: MYC translocation can also increase the expression of a protein known as X-linked inhibitor of apoptosis protein (XIAP), which inhibits caspase-dependent apoptosis. Targeting XIAP may increase the sensitivity of MYC-positive BL cells to apoptosis-inducing drugs [119].
- Notch and MAPK Pathways: Notch pathway was also found to be involved in MYC-driven lymphomagenesis, with MYC translocation upregulating the expression of Notch receptors and ligands, leading to the activation of the Notch pathway [120]. Therefore, targeting the mitogen-activated protein kinase (MAPK) pathway, which is active in MYC-driven malignancies, has shown therapeutic promise [121].
6.2.3. Synthetic Lethality Strategies
6.2.4. Epigenetic Modifiers
6.2.5. Leveraging MYC’s Role in Metabolism
6.2.6. Investigation of MYC Inhibitor OmoMYC
7. Challenges in Targeting MYC
8. Future Directions
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Mechanism | Description |
---|---|
Gene Amplification | This is when there is an increase in the number of copies of the MYC gene, leading to overproduction of MYC protein. |
Chromosomal Translocation | This is when the MYC gene is moved to a different chromosome, often leading to its inappropriate activation. In Burkitt lymphoma, for example, MYC is often translocated to the immunoglobulin heavy or light chain loci, which are highly active regions of the genome. |
Mutation | Mutations in the MYC gene or in the genes that regulate MYC can lead to increased MYC activity. |
Deregulation of Transcriptional Control | Disruptions in the normal mechanisms that control the transcription of the MYC gene can lead to overproduction of the MYC protein. |
Post-transcriptional and Post-translational Modifications | Changes that occur to MYC mRNA or MYC protein after transcription and translation, respectively, can increase the stability, abundance, or activity of MYC. |
Deregulation of MYC Degradation | Normally, MYC protein is rapidly degraded to maintain proper control of its levels. Disruptions in these degradation pathways can lead to increased levels of MYC. |
Mechanism of Action | Type | Drugs |
---|---|---|
Anti-MYC (MYC Proto-Oncogene Protein) | Protein | 6 |
Aurora kinase A (AURKA; ARK1)/c-MYC Interaction Inhibitors | Protein | 4 |
Drugs Targeting MYC Proto-Oncogene Protein Promoter G-quadruplex (MycG4) | Gene | 8 |
Drugs Targeting MYC Transcription Factors | Protein | 12 |
Dual Specificity Mitogen-Activated Protein Kinase 3 (MAP2K3)/c-MYC Interaction Inhibitors | Protein | 1 |
MYC Expression Inhibitors | Gene | 152 |
MYC Proto-Oncogene Protein (c-MYC) Degradation Inducers | Protein | 46 |
MYC Proto-Oncogene Protein (c-MYC) Gene Editing | Gene | 1 |
MYC Proto-Oncogene Protein (c-MYC) Inhibitors | Protein | 159 |
MYC Proto-Oncogene Protein (c-MYC)/MYC-Associated Factor X (Max) Interaction Inhibitors | Protein | 24 |
MYC Proto-Oncogene Protein (MYC)/TRRAP Interaction Inhibitors | Protein | 2 |
Transcription Factor Ligands | Protein | 35 |
WD Repeat-Containing Protein 5 (WDR5; BIG3)/c-MYC Interaction Inhibitors | Protein | 8 |
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Tandon, A.; Kuriappan, J.A.; Dubey, V. Translocation Tales: Unraveling the MYC Deregulation in Burkitt Lymphoma for Innovative Therapeutic Strategies. Lymphatics 2023, 1, 97-117. https://doi.org/10.3390/lymphatics1020010
Tandon A, Kuriappan JA, Dubey V. Translocation Tales: Unraveling the MYC Deregulation in Burkitt Lymphoma for Innovative Therapeutic Strategies. Lymphatics. 2023; 1(2):97-117. https://doi.org/10.3390/lymphatics1020010
Chicago/Turabian StyleTandon, Amol, Jissy Akkarapattiakal Kuriappan, and Vaibhav Dubey. 2023. "Translocation Tales: Unraveling the MYC Deregulation in Burkitt Lymphoma for Innovative Therapeutic Strategies" Lymphatics 1, no. 2: 97-117. https://doi.org/10.3390/lymphatics1020010