Blood Science continues to lead the way in elucidating  complex biological processes and their implications in disease. In this insightful review article, “Dual role of BCL11B in T-cell malignancies,” Grzegorz K. Przybylski, Julia Przybylska, and Yangqiu Li explore the paradoxical functions of the B-cell CLL/lymphoma 11B (BCL11B) gene in T-cell development and malignancies.

Known for its critical role in T-cell development, BCL11B is both a tumor suppressor and an oncogene, depending on the biological context. This duality makes BCL11B a pivotal focus of research, as it presents unique opportunities and challenges for therapeutic intervention in T-cell-related cancers.

A Crucial Player in T-Cell Development

BCL11B, a zinc finger transcription factor, is essential for the proper differentiation and survival of T-cells. It is expressed almost exclusively in T-cell lineages, where it influences α/β T-cell development, thymocyte selection, and responses to developmental checkpoints. Knockout studies in mice reveal that the absence of BCL11B results in a complete lack of T-cell production and early mortality, emphasizing its critical role. Additionally, BCL11B’s involvement extends to non-hematopoietic functions, such as neurogenesis, skin development, and craniofacial formation, although these functions lie beyond the scope of this discussion.

BCL11B as a Tumor Suppressor

The tumor suppressor role of BCL11B is primarily associated with its function in genomic stability. Acting through the base excision repair (BER) pathway, BCL11B enhances the activity of enzymes like NTHL1 glycosylase and Pol β polymerase, which repair oxidative DNA damage. Deficient expression of BCL11B leads to inefficient DNA repair, resulting in mutations that accumulate during T-cell receptor rearrangements in proliferating T-cell progenitors. This genomic instability has been implicated in the initiation of malignancies such as T-cell acute lymphoblastic leukemia (T-ALL).

Evidence supporting the tumor suppressor role includes studies showing BCL11B deletions and mutations in human T-ALL. These alterations disrupt its zinc finger domains, essential for DNA binding and transcriptional regulation, thereby fostering malignancy. Similar findings in murine models demonstrate that BCL11B deletion can lead to radiation-induced thymic lymphomas. These results collectively establish BCL11B as a key player in maintaining genomic integrity and preventing oncogenesis.

The Oncogenic Face of BCL11B

In contrast, BCL11B also functions as an oncogene in established T-cell malignancies. Overexpression of BCL11B has been observed in most T-ALL cases. This overexpression enhances the survival of malignant cells by promoting resistance to chemotherapeutic agents, delaying the cell cycle at G1 phase, and modulating the activity of cyclin-dependent kinase inhibitors. Additionally, BCL11B overexpression silences genes such as SKP2, which are involved in ubiquitin-mediated degradation, and MYCN, which plays a role in cell cycle progression.

Recent studies also reveal that BCL11B overexpression aids in DNA repair, allowing malignant cells to resist DNA-damaging therapies. It has been shown to cooperate with oncogenes like RAS, repairing reactive oxygen species-induced damage and enabling the evasion of senescence. These findings highlight its role in sustaining malignancies and underscore its potential as a therapeutic target.

Chromosomal Rearrangements and Mutations

The oncogenic and tumor suppressor roles of BCL11B are further complicated by chromosomal rearrangements and mutations. In cases of T-ALL, rearrangements such as t(5;14)(q35;q32) juxtapose BCL11B with oncogenic enhancers, driving its overexpression. Other rearrangements result in the fusion of BCL11B with transcriptionally active sequences or enhance the expression of nearby oncogenes like HOXA, NKX2-1, and NKX2-5. While these events contribute to malignancy, the precise effects of BCL11B rearrangements remain insufficiently understood and require further investigation.

Therapeutic Implications of BCL11B Inhibition

Targeting BCL11B in malignancies where it is overexpressed presents a novel therapeutic opportunity. Inhibiting BCL11B disrupts DNA repair in malignant T-cells, leading to apoptosis. Simultaneously, research has shown that suppressing BCL11B in normal T-cells induces their transformation into natural killer-like cells (ITNK) with potent antitumor activity. This dual mechanism offers a promising strategy for combating T-cell malignancies by combining tumor cell eradication with enhanced immune responses.

Despite these exciting prospects, challenges remain. Developing a specific BCL11B inhibitor that selectively targets malignant cells while sparing normal T-cell functions is essential. Additionally, the heterogeneity of BCL11B mutations across different malignancies underscores the need for precision medicine approaches.

Conclusion

The dual role of BCL11B exemplifies the complexity of its functions in T-cell biology and malignancy. While reduced expression compromises genomic stability and facilitates malignant transformation, sustained overexpression in established cancers promotes tumor survival and progression. These opposing roles underscore the importance of context-specific therapeutic strategies.

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https://journals.lww.com/bls/fulltext/2024/10000/dual_role_of_bcl11b_in_t_cell_malignancies.9.aspx