
==== Front
Blood Sci
Blood Sci
BS9
Blood Science
2543-6368
Lippincott Williams & Wilkins Hagerstown, MD

BLS-24-012
00009
10.1097/BS9.0000000000000204
3
Review Article
Dual role of BCL11B in T-cell malignancies
Przybylski Grzegorz K. a*
Przybylska Julia b
Li Yangqiu c*
a Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
b Department of Rheumatology, Independent Public Health Care Facility, Międzychód, Poland
c Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China.
*Address correspondence: Dr. Grzegorz K. Przybylski, Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-461 Poznań, Poland. E-mail: address grzegorz.przybylski@igcz.poznan.pl (G. K. Przybylski); Dr. Yangqiu Li, Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China; E-mail address: yangqiuli@hotmail.com (Y. Li).
17 9 2024
10 2024
6 4 e00204e00204
28 1 2024
13 8 2024
Copyright © 2024 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The zinc finger transcription factor B-cell CLL/lymphoma 11B gene (BCL11B, CTIP2) plays a crucial role in T-cell development, but its role in T-cell malignancies has not yet been definitively clarified. In the literature, 2 contradictory hypotheses on the function of BCL11B exist. One suggests that BCL11B functions as tumor suppressor gene, and the other suggests that BCL11B functions as oncogene. The aim of this review is to revise the current knowledge about the function of BCL11B in T-cell malignancies, confront these 2 hypotheses and present a new model of dual role of BCL11B in T-cell malignancies and potential new therapeutic approach, based on recent findings of the function of BCL11B in DNA damage repair. Decreased BCL11B expression, resulting in deficient DNA repair, may facilitate DNA mutations in rapidly proliferating T-cell progenitors that undergo gene rearrangements, thereby leading to malignant transformation. On the other hand, decreased BCL11B expression and inefficient DNA repair may result in accumulation of DNA damages in genes crucial for the cell survival and in apoptosis of malignant T cells. We hypothesize that T-cell malignancies expressing high levels of BCL11B might be dependent on it. In those cases, targeted inhibition of BCL11B expression may have a therapeutic effect. The antitumor effect of BCL11B suppression might be strengthened by generation of induced T to NK cells (ITNK). Therefore, there is an urgent need to develop a specific BCL11B inhibitor.

BCL11B
BER
CTIP2
Rit1
T-cell malignancy
T-ALL
TCL
OPEN-ACCESSTRUE
==== Body
pmc1. INTRODUCTION

The C(2)H(2) zinc finger transcription factors B-cell CLL/lymphoma 11A (Bcl11a), encoded by the BCL11A (CTIP1) gene, and its paralog Bcl11b encoded by the BCL11B (CTIP2) gene, were first identified in mice in 2000, as binding partners of the chicken ovalbumin upstream promoter-transcription factor (COUP-TF) family of nuclear hormone receptors.1 One year later, human homologs of BCL11A and BCL11B were identified, and localized to chr2p13 and chr14q32.1, respectively.2 Despite substantial similarities in their structure and binding sites,2–4 the 2 factors have distinct biological functions and roles in lymphocyte development. Bcl11a has a broader function in hematopoiesis. It is responsible for the development of B cells but is also involved in the development of dendritic cells and switch from γ- to β-globin expression during the fetal to adult erythropoiesis transition.4–7 In contrast to BCL11A, and to its misleading name, BCL11B is neither expressed in B-cell CLL nor in B-cell lymphoma. In the hematopoietic system, BCL11B is expressed almost exclusively in the T-cell lineage. It is essential for α/β T lymphocytes development; BCL11B knockout mice are born without α/β T cells and die shortly after birth.8–12 BCL11B is crucial for the initial pro-T-cell commitment, positive selection and survival of double-positive thymocytes, lineage choice in postselection thymocytes and correct responses to developmental checkpoints.13–15 It is also responsible for proper function of mature T lymphocytes, and removal of Bcl11b at the double-positive stage of T-cell development or in T(reg) cells causes autoimmune diseases.16,17 Besides T cells, BCL111B is implicated in the development of other nonhematopoietic tissues, including neurogenesis, skin development, adipogenesis, tooth formation, and cranial suture ossification,18,19 but this is beyond the scope of this article.

Although in the last 2 decades many studies have been published on BCL11B, its role in T-cell malignancies has not yet been definitively clarified. The aim of this review is to discuss the 2 contradictory hypotheses on the function of BCL11B in T-cell neoplasms; tumor suppressor; or oncogene.

2. BCL11B ALTERATIONS IN T-CELL MALIGNANCIES

First recurrent chromosomal alteration involving BCL11B, t(5;14)(q35;q32), associated with expression of the TLX3 oncogene, due its juxtaposition to BCL11B, were reported by Bernard et al.20 First rearrangement affecting directly the BCL11B gene was reported by Przybylski et al.21 This rearrangement resulted in the expression of the 5′ part of BCL11B, including exons 1 to 3, fused to the constant region of the T-cell receptor delta gene (TRDC). Since then, many other genetic alterations have been described in T-cell and T/myeloid-mixed phenotype acute leukemia.22 In some cases BCL11B was affected itself, resulting in its overexpression, or the expression of chimeric fusion transcripts (ZEB2-BCL11B fusion), but more frequently, transcriptionally active enhancer sequences, located close to BCL11B, affected the expression of other genes (HOXA, NKX2-1, and NKX2-5), translocated to it.22–25 The effect of chromosomal rearrangements activating known oncogenes is quite evident, but the effect of heterogenous rearrangements affecting BCL11B gene itself is less obvious, and has not yet been sufficiently studied.

3. BCL11B AS TUMOR SUPPRESSOR GENE

Originally, BCL11B was reported by the team of Kominami, as radiation-induced tumor suppressor gene (Rit1).26 Using genome-wide allelic loss analysis, it has been shown that in murine γ-ray-induced thymic lymphomas a region of chromosome 12, containing, at that time, unknown BCL11B gene, was frequently deleted. In subsequent studies, they have found bi-allelic changes of BCL11B in p53-proficient lymphomas, what suggested an association between the presence of functional p53 and inactivation of BCL11B in the lymphoma development.27 Furthermore, introduction of BCL11B into HeLa cells lacking BCL11B expression suppressed cell growth. The authors concluded that loss-of-function mutations of BCL11B contribute to cancer development. On the other hand, the same group showed that mice born with homozygous BCL111B knockout show block of α/β T-cell differentiation and die but do not develop T-cell malignancies.12 In a large study on T-ALL, monoallelic BCL11B deletions or missense mutations were found in 9% (10 of 117) of cases.28 Some of them disrupted the structure of zinc finger domains required for DNA binding. The authors postulated that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation, although this has not been confirmed in functional studies.

4. BCL11B AS ONCOGENE

In ATM−/− mice heterozygous loss of BCL11B reduced lethal thymic lymphoma by suppressing lymphoma progression but not initiation. The suppression was associated with a T cell–mediated immune response, revealing a haploid insufficient function of Bcl11b in immune modulation against lymphoma and offering an explanation for the complex relationship between Bcl11b status with T-ALL prognosis.29 In our recent study, we created mice with heterozygous BCL11B deletion. These mice have a normal life span and do not develop malignancies.30 The hypothesis of the oncogene function of BCL11B is further supported by research of our group, showing that BCL11B is overexpressed in the majority of T-cell acute lymphoblastic leukemia (T-ALL),21 and inhibition of BCL11B using siRNA leads to apoptosis of malignant but not normal T cells.31 This indicates that malignant T cells need BCL11B for their survival. Subsequently, we showed that forced overexpression of BCL11B resulted in markedly increased resistance to radiomimetic drugs, whereas no influence on death-receptor apoptotic pathway was observed.32 Apoptosis resistance triggered by BCL11B overexpression was accompanied by a cell cycle delay caused by accumulation of cells at G1. This cell cycle restriction was associated with upregulation of cyclin-dependent kinase inhibitors. Moreover, the SKP2 gene encoding a protein of the ubiquitin-binding complex responsible for their degradation was repressed and the expression of the MYCN oncogene was silenced. Furthermore, it was shown that enhancer hijacking drives oncogenic BCL11B expression in lineage-ambiguous stem cell leukemia with expression of myeloid and T lymphoid markers. This upregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or amplifications that generate a superenhancer from a noncoding elements distal to BCL11B. These data support the role of BCL11B overexpression as an oncogenic event in leukemia with T-cell markers.33,34 Our studies in human naïve T cells showed increased proliferation upon BCL11B overexpression and reduced proliferation upon its downregulation.35 The data suggest a potential role of BCL11B in tumor survival and encourage developing Bcl11b-inhibitory approaches as a potential tool to specifically target chemoresistant tumor cells. Very recently, we have showed that BCL11B promotes T-ALL cell survival via the XRCC5/C11ORF21 axis.36 These results are in line with our recent data showing better prognosis for patients with T-cell leukemia and lymphoma with BCL11B mutations.37,38 However, this research included a small number of cases with BCL11B mutations, and has to be confirmed in a larger study.

5. ROLE OF BCL11B IN DNA REPAIR

Very recent study on BCL11B involvement in DNA repair provided new important information on role in tumor development. Vickridge et al39 had shown that BCL11B increases the enzymatic activity of NTHL1 glycosylase and Pol β polymerase, responsible for base excision repair (BER) of DNA, by stimulating binding to their substrate. Furthermore, they showed that BCL11B knockdown increases DNA damage, delays the repair of oxidized bases and abasic sites, and increases the spontaneous and radiation-induced mutation rates, thereby leading to apoptosis of malignant cells. Ectopic overexpression of a small, lacking transcription regulation potential, fragment of BCL11B (BCL11B213-560) accelerated DNA repair and increased resistance to oxidative DNA damage. Most interestingly, they showed that overexpressed BCL11B213-560 cooperates with RAS oncogene in primary cell transformation, by repairing DNA damage caused by RAS induced production of reactive oxygen species, and thereby avoiding cellular senescence. The evidence for tumor suppressor or oncogene role of BCL11B has been summarized in Table 1.

Table 1. Evidence for tumor suppressor or oncogene role of BCL11B.

Source of evidence	Tumor suppressor	Oncogene	
Chromosomal rearrangements involving BCL11B20–25	Rearrangements disrupting BCL11B in T-ALL	Rearrangements activating BCL11B in T-ALL	
BCL11B inactivating mutations26–28	Increased rate of oncogenic mutations in T-ALL
Development of radiation-induced T-cell lymphomas	Lead to apoptosis
due to increased rate of mutations in genes necessary for cell survival	
Homozygous BCL11B knockout mice12
Heterozygous BCL11B knockout mice29,30		Block of α/β T-cell differentiation, but no oncogenesis
Do not develop cancer
In ATM−/− mice heterozygous loss of BCL11B reduces lethal thymic lymphoma	
BCL11B suppression
31,35,39		Inhibition of BCL11B using siRNA leads to apoptosis of malignant but not normal T cells
Higher susceptibility to chemotherapeutics	
BCL11B overexpression
21,32–36,39	Introduction of BCL11B into HeLa cells lacking BCL11B expression suppressed cell growth	Increased resistance to chemotherapeutics
Frequent in T-ALL
Overexpressed BCL11B cooperates with RAS oncogene in primary cell transformation	

6. THERAPEUTIC IMPLICATIONS OF THE DUAL ROLE OF BCL11B IN T-CELL MALIGNANCIES

Although BCL11B inactivation plays a role in accumulation of mutations and may be responsible for malignant transformation of T-cell progenitors, in already developed T-cell malignancy it is BCL11B expression that is necessary for the survival of malignant T cells and progression of the disease. This applies only to T-cell leukemia and lymphoma, and probably also to some nonhematopoietic tumors, that express high levels of BCL11B. Those malignant cells are dependent on DNA repair provided by BCL11B, and deprived of this would eventually undergo cell senescence and die. This makes inhibition of BCL11B a new, promising therapeutic approach, in patients with T-cell malignancies expressing high levels of BCL11B. Furthermore, Li et al9 had shown that BCL11B suppression in normal T lymphocytes leads to their transition to induced T to NK cells (ITNK) exhibiting a strong antitumor effect. Therefore, simultaneous inhibiting of BCL11B in malignant and normal T cells could have a synergistic antitumor effect (Fig. 1). To test the usefulness of BCL11B targeted therapy, a specific BCL11B inhibitor has to be developed.

Figure 1. Potential therapeutic effect of BCL11B inhibition in T-cell malignancies. Suppression of BCL11B in malignant T cells results in insufficient DNA repair and thereby to cell senescence and apoptosis.31,35 Additionally, suppression of BCL11B in normal T cells leads to their transition to induced T to NK cells (ITNK) with cytotoxic antitumor activity.9 Both mechanisms synergistically contribute to the death of tumor cells.

7. SUMMARY

Early studies on BCL11B role in T-cell malignancies, mostly based on the deletions and mutations, suggested its tumor suppressor function. Later, more and more evidence was accumulated indicating that BCL11B might act as oncogene. Currently, based on recent findings of the function of BCL11B in base excision repair, it seems that BCL11B has a dual role in BCL11B malignancies. On the one hand, decreased BCL11B expression resulting in inefficient DNA repair, especially in rapidly proliferating and undergoing T-cell receptor genes rearrangements T-cell progenitors, may facilitate DNA lesions and lead to malignant transformation. On the other hand, decreased BCL11B expression and inefficient DNA repair may result in further accumulation of DNA damages in genes crucial for the cell survival, and result in apoptosis of malignant T cells.

It can be hypothesized that a fraction of T-cell malignancies, most likely those expressing high levels of BCL11B, might be dependent on it. In those cases inhibition of BCL11B might be a promising therapeutic approach, especially if generated by this ITNK cells will show antitumor activity.

ACKNOWLEDGMENTS

This work was supported in part by the National Centre for Research and Development, Poland (No. WPC/BCL/2019) and the Intergovernmental International Cooperation on Scientific and Technological Innovation Project of Chinese Ministry of Science and Technology (No.2017YFE0131600).

Conflict of interest: The authors declare that they have no conflict of interest.

Conflict of interest: The authors declare that they have no conflict of interest.

This work was supported in part by the National Centre for Research and Development, Poland (No. WPC/BCL/2019) and the Intergovernmental International Cooperation on Scientific and Technological Innovation Project of Chinese Ministry of Science and Technology (No. 2017YFE0131600).
==== Refs
REFERENCES

[1] Avram D Fields A Pretty On Top K Nevrivy DJ Ishmael JE Leid M . Isolation of a novel family of C(2)H(2) zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors. J Biol Chem 2000;275 (14 ):10315–10322.10744719
[2] Satterwhite E Sonoki T Willis TG . The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood 2001;98 (12 ):3413–3420.11719382
[3] Avram D Fields A Senawong T Topark-Ngarm A Leid M . COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein. Biochem J 2002;368 (Pt 2 ):555–563.12196208
[4] Liu N Hargreaves VV Zhu Q . Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell 2018;173 (2 ):430–442.e17.29606353
[5] Ippolito GC Dekker JD Wang YH . Dendritic cell fate is determined by BCL11A. Proc Natl Acad Sci U S A 2014;111 (11 ):E998–1006.24591644
[6] Liu P Keller JR Ortiz M . Bcl11a is essential for normal lymphoid development. Nat Immunol 2003;4 (6 ):525–532.12717432
[7] Yu Y Wang J Khaled W . Bcl11a is essential for lymphoid development and negatively regulates p53. J Exp Med 2012;209 (13 ):2467–2483.23230003
[8] Ikawa T Hirose S Masuda K . An essential developmental checkpoint for production of the T cell lineage. Science 2010;329 (5987 ):93–96.20595615
[9] Li P Burke S Wang J . Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science 2010;329 (5987 ):85–89.20538915
[10] Li L Leid M Rothenberg EV . An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 2010;329 (5987 ):89–93.20595614
[11] Kominami R . Role of the transcription factor Bcl11b in development and lymphomagenesis. Proc Jpn Acad Ser B Phys Biol Sci 2012;88 (3 ):72–87.
[12] Wakabayashi Y Watanabe H Inoue J . Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. Nat Immunol 2003;4 (6 ):533–539.12717433
[13] Albu DI Feng D Bhattacharya D . BCL11B is required for positive selection and survival of double-positive thymocytes. J Exp Med 2007;204 (12 ):3003–3015.17998389
[14] Kastner P Chan S Vogel WK . Bcl11b represses a mature T-cell gene expression program in immature CD4(+)CD8(+) thymocytes. Eur J Immunol 2010;40 (8 ):2143–2154.20544728
[15] Kojo S Tanaka H Endo TA . Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes. Nat Commun 2017;8 (1 ):702.28951542
[16] Lorentsen KJ Cho JJ Luo X . Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma. Nat Commun 2018;9 (1 ):1679.29700302
[17] Vanvalkenburgh J Albu DI Bapanpally C . Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. J Exp Med 2011;208 (10 ):2069–2081.21875956
[18] Daher MT Bausero P Agbulut O Li Z Parlakian A . Bcl11b/Ctip2 in skin, tooth, and craniofacial system. Front Cell Dev Biol 2020;8 :581674.33363142
[19] Lennon MJ Jones SP Lovelace MD Guillemin GJ Brew BJ . Bcl11b-A critical neurodevelopmental transcription factor-roles in health and disease. Front Cell Neurosci 2017;11 :89.28424591
[20] Bernard OA Busson-LeConiat M Ballerini P . A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia. Leukemia 2001;15 (10 ):1495–1504.11587205
[21] Przybylski GK Dik WA Wanzeck J . Disruption of the BCL11B gene through inv(14)(q11.2q32.31) results in the expression of BCL11B-TRDC fusion transcripts and is associated with the absence of wild-type BCL11B transcripts in T-ALL. Leukemia 2005;19 (2 ):201–208.15668700
[22] Di Giacomo D La Starza R Gorello P . 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia. Blood 2021;138 (9 ):773–784.33876209
[23] Liu Y Easton J Shao Y . The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 2017;49 (8 ):1211–1218.28671688
[24] Nagel S Scherr M Kel A . Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3’-BCL11B enhancers and coregulation by PU.1 and HMGA1. Cancer Res 2007;67 (4 ):1461–1471.17308084
[25] Su X Drabkin H Clappier E . Transforming potential of the T-cell acute lymphoblastic leukemia-associated homeobox genes HOXA13, TLX1, and TLX3. Genes Chromosomes Cancer 2006;45 (9 ):846–855.16804919
[26] Matsumoto Y Kosugi S Shinbo T . Allelic loss analysis of gamma-ray-induced mouse thymic lymphomas: two candidate tumor suppressor gene loci on chromosomes 12 and 16. Oncogene 1998;16 (21 ):2747–2754.9652741
[27] Wakabayashi Y Inoue J Takahashi Y . Homozygous deletions and point mutations of the Rit1/Bcl11b gene in gamma-ray induced mouse thymic lymphomas. Biochem Biophys Res Commun 2003;301 (2 ):598–603.12565905
[28] Gutierrez A Kentsis A Sanda T . The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood 2011;118 (15 ):4169–4173.21878675
[29] Pinkney KA Jiang W Lee BJ . Haploinsufficiency of Bcl11b suppresses the progression of ATM-deficient T cell lymphomas. J Hematol Oncol 2015;8 :94.26219558
[30] Przybylski GK Korsak D Izykowska K . Generation of inducible BCL11B knockout in TAL1/LMO1 transgenic mouse T cell leukemia/lymphoma model. Int J Mol Sci 2022;23 (9 ):4932.35563322
[31] Grabarczyk P Przybylski GK Depke M . Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells. Oncogene 2007;26 (26 ):3797–3810.17173069
[32] Grabarczyk P Nahse V Delin M . Increased expression of bcl11b leads to chemoresistance accompanied by G1 accumulation. PLoS One 2010;5 (9 ):e12532.20824091
[33] Montefiori LE Bendig S Gu Z . Enhancer hijacking drives oncogenic BCL11B expression in lineage-ambiguous stem cell leukemia. Cancer Discov 2021;11 (11 ):2846–2867.34103329
[34] Montefiori LE Mullighan CG . Redefining the biological basis of lineage-ambiguous leukemia through genomics: BCL11B deregulation in acute leukemias of ambiguous lineage. Best Pract Res Clin Haematol 2021;34 (4 ):101329.34865701
[35] Chen S Huang X Chen S . The role of BCL11B in regulating the proliferation of human naive T cells. Hum Immunol 2012;73 (5 ):456–464.22426257
[36] Yu X Li Y Yang P . BCL11B promotes T-cell acute lymphoblastic leukaemia cell survival via the XRCC5/C11ORF21 axis. Clin Transl Med 2024;14 (2 ):e1580.38317587
[37] Chen C Huang L Liu S . T-cell lymphoma patient harboring BCL11B mutations had favorable overall survival. Asia Pac J Clin Oncol 2023;20 (1 ):81–86.37635422
[38] Chen C Zhang Y Zeng X Zeng C Przybylski GK Li Y . BCL11B mutations are associated with higher CD8+ T-cell percentage and favorable clinical outcomes in patients with T-cell acute lymphoblastic leukemia. Clin Med Insights Oncol 2023;17 :11795549231216427.38058602
[39] Vickridge E Faraco CCF Lo F . The function of BCL11B in base excision repair contributes to its dual role as an oncogene and a haplo-insufficient tumor suppressor gene. Nucleic Acids Res 2024;52 (1 ):223–242.37956270
