TBL1XR1 in Physiological and Pathological States J

Donald and Barbara Zucker School of Medicine Journal Articles Academic Works

2015 TBL1XR1 in physiological and pathological states J. Y. Li Hofstra Northwell School of Medicine

G. Daniels

J. Wang Northwell Health

X. Zhang Hofstra Northwell School of Medicine

Follow this and additional works at: https://academicworks.medicine.hofstra.edu/articles Part of the Pathology Commons

Recommended Citation Li J, Daniels G, Wang J, Zhang X. TBL1XR1 in physiological and pathological states. . 2015 Jan 01; 3(1):Article 713 [ p.]. Available from: https://academicworks.medicine.hofstra.edu/articles/713. Free full text article.

This Article is brought to you for free and open access by Donald and Barbara Zucker School of Medicine Academic Works. It has been accepted for inclusion in Journal Articles by an authorized administrator of Donald and Barbara Zucker School of Medicine Academic Works. Am J Clin Exp Urol 2015;3(1):13-23 www.ajceu.us /ISSN:2330-1910/AJCEU0008636

Review Article TBL1XR1 in physiological and pathological states

Jian Yi Li1, Garrett Daniels2, Jing Wang1, Xinmin Zhang1

1Department of Pathology and Laboratory Medicine, Hofstra North Shore-LIJ School of Medicine, New York, USA; 2Department of Pathology, New York University School of Medicine, New York, USA Received March 31, 2015; Accepted April 1, 2015; Epub April 25, 2015; Published April 30, 2015

Abstract: Transducin (beta)-like 1X related protein 1 (TBL1XR1/TBLR1) is an integral subunit of the NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) repressor complexes. It is an evolutionally conserved protein that shares high similarity across all species. TBL1XR1 is essential for transcriptional repression mediated by unliganded nuclear receptors (NRs) and othe regulated transcription factors (TFs). However, it can also act as a transcription activator through the recruitment of the ubiquitin-conjugating/19S proteasome complex that mediates the exchange of corepressors for coactivators. TBL1XR1 is required for the activation of multiple intracellular signaling pathways. TBL1XR1 germline mutations and recurrent mutations are linked to intellectual disability. Upregulation of TBL1XR1 is observed in a variety of solid tumors, which is associated with advanced tumor stage, metastasis and poor prognosis. A variety of genomic alterations, such as translocation, deletion and mutation have been identified in many types of neoplasms. Loss of TBL1XR1 in B-lymphoblastic leukemia disrupts glucocorticoid receptor recruitment to chromatin and results in glucocorticoid resistance. However, the mechanisms of other types of genomic changes in tumorogenesis are still not clear. A pre-clinical study has shown that the disruption of the interaction between TBL1X and β-catenin using a small molecule can inhibit the growth of AML stem and blast cells both in vitro and in vivo. These findings shed light on the therapeutic potentials of targeting TBL1XR1 related proteins in cancer treatment.

Keywords: TBL1XR1, TBL1X, corepressor, coactivator, targeted therapy

Introduction mediates the exchange of corepressors for coactivators [6, 7]. TBL1XR1 is essential in the Transducin (beta)-like 1X related protein 1 (TBL- activation of Wnt-β-catenin and NF-κB signaling 1XR1), also known as TBLR1, is an F-box/ pathways [6-10]. De novo deletions and recur- WD40-repeat containing protein that was origi- rent mutations have been identified in nally isolated as a gene transcript that is prefer- TBL1XR1gene, which are linked to intellectual entially expressed in human CD34+CD38- cells disability (ID) [11-15]. Accumulating evidence [1]. Biochemical studies identified TBL1XR1 as suggests that TBL1XR1 may play an important a core component of NCoR (nuclear receptor role in tumorigenesis, invasion, metastasis, and corepressor) and SMRT (silencing mediator of developing resistance to therapies [16-22]. This retinoic acid and thyroid hormone receptors) review will focus on the genomic structure, repressor complexes that also contain HDAC3 expression, and functions of TBL1XR1 and the (histone deacetylase 3), TBL1X (transducin pathological states associated with its dysregu- (beta)-like 1X), and GPS2 (G-protein pathway lation. We will also discuss the therapeutic suppressor 2) [2, 3]. TBL1XR1 is essential in potentials of targeting TBL1XR1 and related targeting SMRT/NCoR corepressor complexes pathways. to the promoter of target genes by unliganded nuclear receptors (NRs) and other regulated TBL1XR1 family transcription factors (TFs) to mediate repression [3-5]. On the other hand, TBL1XR1 is also Human TBL1XR1 (hTBL1XR1/hTBLR1/IRA1) required for transcriptional activation by ligan- gene is located on chromosome 3q26.32 and ded NRs and other TFs. It serves as a specific consists of 18 exons spanning 178, 119 base adaptor for the recruitment of the ubiquitin- pairs [23]. Two closely related genes, TBLR1X conjugating/19S proteasome complex that and TBL1Y, have been cloned and mapped to The role of TBL1XR1 human chromosome X and Y, respectively [24, TBL1XR1 is also susceptible for posttransla- 25]. TBL1XR1 mRNA is ubiquitously expressed tional modifications, including phosphoration in many human tissues with higher levels of and sumoylation. It contains two putative phos- expression observed in thyroid, prostate and phorylation sites (one for CK1/GSK3 and one breast tissues. The expression of TBL1XR1 for PKCδ) and one SUMO modification site overlaps but is distinct from that of TBL1X and (Lys497) [7, 9]. Multiple microRNAs (miRNAs) TBL1Y. In addition, an alternatively spliced form targeting TBL1XR1 have been identified by of TBL1XR1 (TBLR1β) has been demonstrated using computational prediction programs, of in human material and it too has a unique pat- which hsa-miR-205 is found to be functional tern of expression [23]. The murine homologue [30]. In addition, several potential long non- is structurally similar and is also located on coding RNA (lncRNA) sequences are identified Chromosome 3. Only one isoform has been in the region encompassing the hTBL1XR1 identified in Drosophila (Ebi) and Xenopus gene. Further studies are needed to under- (Xenopus TBL1XR1), which are found more stand the roles of these miRNAs and lncRNAs similar to hTBL1XR1 than to hTBL1X [4, 26]. in the function and regulation of TBL1XR1.

The hTBL1XR1 gene encodes a 514 amino acid TBL1XR1 is primarily localized in nucleus in tis- protein with an estimated molecular mass of sues and many cell lines. However, we have 55.5 kDa. The β isoform of hTBL1XR1 encodes shown that TBL1XR1 is mostly located in the a larger protein due to disruption of translation cytosol of NIH-3T3 cells and translocates to the by alternative splicing. TBL1XR1 protein con- nucleus after induction of apoptosis or growth tains a LisH domain (Lis1 homology domain) arrest. The cytoplasmic pattern is also observed and a F-box-like domain at the amino-terminus in several prostate cancer cell lines and prima- and seven WD40 repeats at the carboxy-termi- ry prostate cancer cells [21, 23]. nus [23]. The LisH domain is required for oligo- Normal functions of TBL1XR1 merization, transcriptional repression, and binding to hypoacetalyted H2B and H4 [27]. TBL1XR1 acts as a transcriptional corepressor Deletion of LisH domain decreases the half life of TBL1XR1 protein and results in its transloca- Transcriptional repression mediated by unligan- tion from nucleus to cytoplasm [28]. The F-box- ded NRs or other TFs requires a group of core- like domain is essential for the recruitment of pressors. Biochemical purifications have identi- the ubiquitin/19S proteasome complex to the fied multiple corepressor complexes [2, 3, 31], transcription units regulated by NRs and TFs for which may be used combinatorially and recruit- the degradation of SMRT/NCoR corepressor. It ed to chromatin in a sequential fasion [7]. The is also important for the ubiquitin-mediated best characterized is the SMRT/N-CoR/HDAC3 degradation of other proteins [28]. The WD40 complex that also contains TBL1X, TBL1XR1, domains are important for self or heterodimer and GPS2 [2, 3]. The corepressor complexes protein-protein interaction. The first WD repeat actively silence basal transcription through in TBL1XR1 is essential for its binding to the interaction with unliganded NRs. However, the RD4 domain of NCoR [3]. interaction alone is not sufficient for targeting the corepressor complexes to target gene pro- The structure of TBL1XR1 family is evolution- moters and mediating transcriptional repres- arily conserved with high degrees of similarity sion. As a subunit of the SMRT/NCoR repressor from yeast to human at the amino acid level complexes, TBL1XR1 is found to be essential [29]. The N-terminal sequence is totally con- for repression by unliganded NRs in both served between Xenopus TBL1XR1 and human cell lines and Xenopus oocytes [3, 4]. A hTBL1XR1 and 94% identical to that of hTBL1X. recent study using small interfering RNA (siRNA) The WD-40 repeat domain is 98% identical revealed that TBL1XR1 and TBL1X are func- between Xenopus TBL1XR1 and hTBL1XR1 tionally redundant and essential for transcrip- whereas only 90% identical between the two tional repression by thyroid hormone receptor human proteins. The high degrees of similarity (THR). Both TBL1XR1 and TBL1X are able to in TBL1XR1 family across all the species sug- directly bind to NCoR and SMRT through their gest similar biochemical and molecular func- N-terminal and first WD-40 domains. They do tions [4, 23]. not have direct interaction with unliganded THR

14 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1 and HDAC3. They are critical for targeting the induced by the activation of Toll-Like Receptors SMRT/NCoR corepressor complexes to chro- (TLRs) [33]. Our early study showed that matin through binding hypoacetylated histones TBL1XR1 is also required for the degradation of H2B and H4. Furthermore, this study proposes SMRT [23]. Additionally, the phosphorytion of a two-interaction, feed-forward working model SMRT S2410 by IKKα is important for the dis- for targeting SMRT/N-CoR complexes to chro- missal of SMRT for the derepression of NF-κB matin. In brief, the interaction between SMRT/ target genes, which concomitantly correlates NCoR and unliganded NRs initiates limited his- with the recruitment of TBL1XR1/TBL1X to the tone deacetylation at the target gene promoter target gene promoters, suggesting that TBL- sites. TBL1X/TBL1XR1 then stabilizes the 1XR1 is also important in the dismissal of the association of the SMRT/NCoR complexes with SMRT complex for coactivator exchange [10]. chromatin by binding the deacetylated his- Many signaling pathways in the higher eukary- tones, resulting in deacetylation of additional otes are tightly regulated through a dual-repres- histones. In the final step, the formation of sta- sion “checkpoint” based on distinct corepres- ble complexes and extensive deacetylation sor complexes. The dedicated exchange factors lead to intiation and maintenance of repres- such as TBL1XR1 and TBL1X serve as sensors sion. These studies implicate the critical roles for signal-specific dismissal of distinct core- of TBL1XR1 in the formation of stable corepres- pressors, with specificity imposed by upstream sor complexes on chromatin for mediating signaling pathways [7]. repression [27, 32]. TBL1XR1 in Wnt-β-catenin signaling pathway TBL1XR1 acts as an exchange factor of corepressors for coactivators The Wnt-β-catenin signaling pathway is critical for development, specification of cell fate, and Transcriptional activation mediated by liganded adult stem cell proliferation. The aberrant acti- NRs and other regulated TFs requires the dis- vation of this pathway has been implicated in missal of corepressors followed by the recruit- the tumorogenesis of several types of cancers ment of a series of coactivator complexes har- [34]. The Wnt target genes are silenced by the T boring specific enzymatic activities. Although cell factor/lymphoid enhancing factor (TCF/ TBL1XR1 and TBL1X are intrinsic components LEF) family protein and Groucho/TLE1 core- of the SMRT/NCoR corepressor complexes, pressor complex in the absence of signaling. recent study has shown that they both are Upon activation of the Wnt-β-catenin signals, required for transcriptional activation by estro- β-catenin enters the nucleus and binds to the gen receptor (ER), androgen receptor (AR), THR, TCF/LEF protein in displacing the corepressor and peroxisome proliferator-activated receptor complexes and recruiting other co-activator (PPAR). The activation by RAR (retinoid acid complexes to induce transcription [8, 9, 34]. receptor) and AP-1 (activator protein-1) depends Overexpression of TBL1XR1 or TBL1X in exclusively on TBL1XR1 [6, 7]. TBL1XR1 and HK293T cells can lead to significantly enhanced TBL1X both serve as specific adaptors for the β-catM (a mutant form of β-catenin)-stimulated recruitment of the ubiquitin conjugating/19S transcription. Depletion of TBL1XR1 or TBL1X proteasome complex to the promoter in a liga- by siRNAs abolishes the activation of β-catenin nd-dependent fashion, mediating the exchange induced by lithium (LiCl) treatment or Wnt3a. of corepressors for coactivatores [6, 7]. Unlike Wnt signaling induces the formation of a com- TBL1XR1, TBL1X is still required for the tran- plex between β-catenin and TBL1X-TBL1XR1, scriptional activation by NRs in the absence of which is recruited to the Wnt target gene pro- NCoR and SMRT. The data indicate that moter. TBL1X can also bind to TCFs. The recruit- TBL1XR1 is specifically required for the ubiqui- ment of TBL1X-TBL1XR1 and β-catenin to the tylation and degradation of NCoR and TBL1X Wnt target gene promoter is mutually depen- may act on different corepressor complexes. dent. Furthermore, TBL1X andTBL1XR1 do not Further study identified CtBP1/2 as a specific affect the nuclear level of β-catenin and are not target of TBL1X [7]. The functions and the spec- responsible for degradation of corepressor ificity of TBL1XR1 and TBL1X are regulated by complexes. These findings indicate that unlike signaling specific phosphoration events at tar- their roles as exchange factors in NR-mediated get gene promoters [7]. This differential speci- activation, TBL1X and TBL1XR1 are critical for ficity is also observed in the NCoR clearance the recruitment of β-catenin to Wnt target gene

15 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1 promoters. TBL1X and TBL1XR1 are also TBL1XR1/HDAC3 corepressor complex is important for β-catenin mediated oncogenesis important for mitotic spindle formation [8]. Recent study shows that both TBL1X and TBL1XR1 are subjected to sumoylation in a Wnt Studies have shown that altered HDAC3 level signaling-dependent manner, which dismisses increases G(2)/M cells, suggesting a possible TBL1X-TBL1XR1 from the NCoR complex and role of HDAC3 in cell proliferation. Ishii et al [37] enhances the formation of TBL1X-TBL1XR1-β- showed that the HDAC3 complex, including catenin complex [9]. The depletion of TBL1X- N-CoR, TBL1X, and TBL1XR1, is localized on TBL1XR1 or Inhibition of sumoylation may have the mitotic spindle. Knockdown of HDAC3 or important implications in developing new strat- N-CoR or inhibition of HDAC3 activity with egies for inhibiting Wnt-beta-catenin-mediated Trichostatin A results in a collapsed mitotic tumorigenesis. spindle independent of transcriptional regulation, which can be rescued by wild-type HDAC3. TBL1XR1 in NF-κB pathway Inactivation of HDAC3 impairs kinetochore- microtubule attachments without affecting the NF-κB plays an important role in multiple cellu- kinetochores and the spindle assembly check- lar processes, including immune signaling, point. The studies suggest that acetylation- inflammation, development, proliferation and deacetylation of mitotic spindle components survival. Aberrant activation of NF-κB signaling may be essential for mitotic spindle function. pathway has been implicated in autoimmunity, chronic inflammation and cancer [35]. In TBL1XR1 in normal hematopoiesis unstimulated cells, NF-κB is sequested in cyto- + - plasm as an inactive form by binding to a family CD34 CD38 cells are considered as the earli- of inhibitory proteins, IkB. Upon stimulation, IkB est human hematopoietic progenitors. They is phosphorylated by IkB kinase (IKK) complex have the ability to initiate long term bone mar- and subject for subsequent proteasome-medi- row culture in vitro and to reconstitute NOD/ ated degradation, allowing NF-κB to translocate SCID mice in vivo [38, 39]. We have found that to the nucleus to initiate transcription [35]. In TBL1XR1 is expressed at a much higher level in CD34+CD38- cells compared to their mature unstimulated cells, p50 or p52 homodimers + + repress NF-κB regulated genes through BCL-3 counterpart CD34 CD38 cells. Northern blot dependent and BCL-3 independent mecha- analysis has shown that TBL1XR1 mRNA is nisms. The activation of NF-κB regulated genes expressed at a higher level in the tissues is mediated by the exchange of BCL-3- enriched for early hematopoietic cells such as fetal liver and bone marrow in comparison with associated NCoR corepressor for the Tip60 peripheral blood [23]. TBL1XR1 has been impli- coactivator complex. This pathway only regu- cated in multiple intacellular signaling path- lates a small subset of NF-κB regulated genes ways important for stem cell fate determination while the majority of NF-κB regulated genes are and proliferation such as Wnt pathway and regulated by the classical NF-κB heterodimer NOTCH pathway. Ebi, the Drosophila homo- complex [10]. Recent study reveals that both logue of TBL1XR1, is required for maintenance TBL1X and TBL1XR1 are required for the NF-κB of photoreceptor neurons by suppressing pro- mediated activation on canonical sites [6]. apoptotic gene expression [40]. This is con- TBL1X is critical for the recruitment of p65 to firmed by a recent report that TBL1XR1 mRNA NF-κB target genes to mediate activation. is upregulated after the exposure of neural NF-κB transcription requires IKKalpha to phos- stem cells to ethanol [41]. We have shown that phorylate SMRT on chromatin, stimulating the overexpression of TBL1XR1 is able to induce exchange of corepressor for coactivator com- growth arrest [23]. These findings suggest that plexes. The recruitment of TBL1X-TBL1XR1 to TBL1XR1 may be important in the maintenance the target promoters coincides with SMRT of hematopoietic stem cells. Further studies in phosphorylation [10]. Moreover, TBL1XR1 can this regard may be helpful in our understanding directly interact with BCL-3 and is involved in its functions in hematopoiesis. BCL-3 degradation through a GSK3 independent pathway [36]. These results suggest that TBL1XR1 and intellectual disability TBL1XR1 plays a critical role in NF-κB mediated activation through both canonical and non- Intellectual Disability (ID) affects almost 3% of canonical pathways. the population and increasingly becomes a

16 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1 public health challenge [11]. It can be sporadic teria for ASD. The mutation data replicate the or associated with other congenital abnormali- importance of a β-catenin-chromatin-remode- ties. Pons et al. reported an eight-year-old girl ling network to ASD etiology [14]. with facial dysmorphism, speech delay, and mild to moderate ID. Her mother displayed simi- TBL1XR1 in cancers lar physical and intellectual features. Using array-CGH (array comparative genomic hybrid- TBL1XR1 dysregulations in solid tumors ization) techniques, a 708 kb microdeletion at Liu et al. identified TBL1XR1 as a differentially 3q26.32 region was identified in both patients, expressed gene in human primary lung squa- which affects only TBL1XR1gene. Family stud- mous cell carcinoma (LSCC) by comparing lung ies revealed that the mother is a founder and tumor tissues and normal bronchial epithelial the pattern of inheritance is autosomal domi- tissues using suppression subtractive hybrid- nant [11]. The third case is a six-year-old girl ization method [15]. Quantitative real-time PCR and she also has facial dysmorphism and mild (q-PCR) analysis showed upregulation of to moderate ID. In this patient, a 1.6 Mb dele- TBL1XR1 mRNA in 75% of LSCC cases in the tion is identified in the 3q26.31q26.32 region validation set. The overexpression of TBL1XR1 encompassing only TBL1XR1 gene [12]. The protein was confirmed by western blot analysis three cases are very similar and possibly repre- in 53.3% of LSCC tumor samples, 5 lung cancer sent a new autosomal dominant syndrome cell lines, and 1 human immortalized bronchial associated with TBL1XR1 haploinsufficiency. epithelial cell line [15]. Deletions at human This syndrome is characterized by facial dys- 3q26.32 encompassing TBL1XR1 gene have morphism (pointed chin, long philtrum, and thin been previously detected by array-based com- vermilion), speech delay, mild to moderate ID, parative genomic hybridization (aCGH) in and lack of autistic behaviors. human immortalized bronchial cell lines.

Additionally, two cases are also identified in the To identify genetic events implicating in cancer DECIPHER database [11]. The first patient has progression, Kadota et al. conducted a compre- autism, hearing impairment and spotty hyper- hensive genetic evaluation of 161 primary pigmentation, who carries a 2.14 Mb deletion breast tumors (mostly invasive breast carcino- encompassing the TBL1XR1 and KCNMB2 mas) for gene amplifications [16]. Their findings genes. The second case is characterized by ID, show that the level of TBL1XR1 protein is high- ataxia, ASD (stereotypic behavior and self-muti- er in the malignant cell lines MCF10CA1h and lation) and dysmorphism (wide mouth, macro- MCF10CA1a than that in MCF10A, a normal tia, prominent ears, hypertelorism, and down- immortalized mammary epithelial cell line. slanted palpebral fissures). This patient carries Depletion of TBL1XR1 in MCF10CA1h using four copy number variation (CNV) affecting sev- shRNA results in reduction of cell migration and eral genes in addition to a 150 kb de novo dele- invasion as well as suppression of tumorigene- tion encompassing only TBL1XR1. sis in mouse xenografts [16]. A different study confirms these findings by showing that Recently, a whole exome sequencing (WES) TBL1XR1is significantly upregulated in breast study identified recurrent mutations in patients cancer cell lines and 52.8% of primary breast with autistic spectrum disorder (ASD), in which cancers cases in comparison with normal two had de novo TBL1XR1 mutations [14]. Both breast tissues. This study also shows that the patients have ASD and severe ID, but neither of level of TBL1XR1 protein expression is positive- them have any obvious dysmorphism or recur- ly correlated with aggressive clinical behavior. rent comorbidities. The TBL1XR1 mutations The patients with higher levels of TBL1XR1 occur at positions 282 (p.Leu282Pro) and 397 expression have shorter overall survival com- (p.Ile397Serfs*19), respectively. The third case pared to those with lower levels of expression. is a Japanese girl who had a de novo TBL1XR1 Multivariate analysis indicates that TBL1XR1 mutation (p.Gly70Asp) located in the F-box-like overexpression is an independent prognostic domain [13]. She presented with West syn- indicator for the survival of breast cancer drome, Rett syndrome-like and autistic fea- patients. They demonstrate that TBL1XR1 pro- tures. Based on the guidelines in the diagnostic motes tumor cell proliferation and tumorigenic- manual (DSM-IV) of the American Psychiatric ity in breast cancer through the activation of Association, this case meets the diagnostic cri- Wnt/β-catenin signaling pathway [17].

17 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1

Similar findings are also observed in cervical amplification has been identified in invasive cancer, nasopharyngeal carcinoma (NPC) and prostate cancer, which correlates with disease esophageal squamous cell carcinoma (ESCC) progression. PTEN loss is the most frequent [18-20]. Upregulation of TBL1XR1 in NPC cells aberration in progressers (57%); followed by leads to resistance of the tumor cells to cispla- TBL1XR1 gain (29%) and MYC gain (14%). tin by activating the NF-κB pathway, which is Based on this study, it would detect progress- associated with poor prognosis [19]. In cervical ers with 86% sensitivity and 100% specificity cancer, upregulation of TBL1XR1 is significantly using a probe set consisting of PTEN, MYC, and associated with recurrence. Forced expression TBL1XR1 [43]. of TBL1XR1 in cervical cancer cell lines (Hela and Siha) promotes invasion by inducing epi- Four novel translocations involving the TBL1- thelial-mesenchymal transition through the XR1 gene have been identified in an effort to activation of NF-κB and Wnt/β-catenin signal- study the landscape of kinase fusion in cancers ling pathways [18]. TBL1XR1 promotes lym- [44]. They include one TBL1XR1-RET fusion phangiogenesis and lymphatic metastasis in and three TBL1XR1-PIK3CA fusions. Two of the ESCC by inducing the expression of VEGF-C. TBL1XR1-PIK3CA fusions are found in 1,072 The association between the TBL1XR1 expres- breast cancer (invasive) samples and one in sion and VEGF-C expression is not only seen in 335 prostate adenocarcinoma samples. Both ESCC but also observed in gastric, colonic and tissue types are hormone driven and ranked breast cancers based on the published data- among the highest for TBL1XR1 mRNA expres- base [20]. sion across all normal tissues. The LisH motif in TBL1XR1 is capable of dimerization, therefore Studies have shown that depletion of TBL1XR1 likely leading to RET or PIK3CA activation. by shRNA in HT-29 cells, a colon cancer cell line significantly reduces the recruitment of β-ca- TBL1XR1 dysregulation in lymphomas tenin to its target gene promoters, such as AXIN2 and c-MYC, and inhibits the endogenous Using WES approach, a novel TBL1XR1/TP63 expression of c-MYC, MMP7 and ITF2, leading gene fusion has been recently identified in dif- to inhibition of tumor cell invasion through the fuse large B-cell lymphoma (DLBCL) [45], Matrigel-coated membrane and suppression of peripheral T-cell lymphoma (PTCL) [46], and fol- tumor growth in nude mice [8]. licular lymphoma (FL) [45]. The gene fusions result from a chromosomal rearrangement Our studies have shown that TBL1XR1acts as a between TBL1XR1 gene (3q26.32) and TP63 coactivator of Androgen receptor (AR) in pros- gene (3q28). In most cases, the exons 1-7 of tate cancer cells and the activation is depen- TBL1XR1 fuse in frame to the exons 4-8 or 4-10 dent on both phosphorylation and 19S protea- of TP63. The exon 14 or exon 4 of TBL1XR1 is some machinery. We also show that TBL1XR1 involved in the remaining cases including two physically interacts with AR and directly occu- DLBCLs and one FL [45]. The TBL1XR1/TP63 pies the androgen-response elements of the fusion is reported in 5% of germinal center affected AR target genes in an androgen- B-cell like (GCB) DLBCL and appears to be dependent manner. TBL1XR1 is primarily local- exclusive for the GCB type. It is also present in ized in the nucleus in benign prostate cells and PTCL in a similar percentage, but this fusion is nuclear expression is significantly reduced in rare event in FL. P63 has two main classes of prostate cancer cells in culture. Similarly, in isoforms, TAp63 and ΔNp63. TAp63 has an human tumor samples, the expression of N-terminal transactivation domain with tumor TBLR1 in the nucleus is significantly reduced in suppressor activity, whereas ΔNp63 contains a the malignant glands compared with the sur- truncated N-terminal domain that has been rounding benign prostatic glands. Stable ecto- proposed to confer oncogenic properties. The pic expression of nuclear TBL1XR1 leads to expression of the TBL1XR1/TP63 fusion was androgen-dependent growth suppression of 5.2 fold higher than the wild-type [45]. The prostate cancer cells in vitro and in vivo by TBL1XR1/TP63 protein may function similarly selective activation of androgen-regulated to ∆N-TP63, antagonizing the action of TP53, genes associated with differentiation and TA-TP63, and TA-TP73. TP63 rearrangement in growth suppression, but not cell proliferation of PTCLs is associated with significantly higher the prostate cancer [21, 42]. TBL1XR1 gene mean immunohistochemistry scores for p63,

18 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1 ki67 and CD30. Patients with PTCLs carrying TBL1XR1 mRNA is significantly under-expre- TP63 rearrangements have significantly inferior ssed and deletion of TBL1XR1 compromised overall survival compared with patients without the function of SMRT/N-CoR in the appropriate TP63 rearrangements. In one case, the fusion control of gene expression [52-54]. Deletions was retrospectively found in T cells before the of TBL1XR1 are significantly more common in clinical diagnosis of mycosis fungoides, sug- B-ALL patients who relapse compared with gesting that it is an initiating event in lympho- those remaining in complete remission. Re- magenesis [47]. It has been speculated that cently, a study has shown that knockdown of this abnormality may not only provide a prolif- TBL1XR1 in B-ALL cell lines results in reduced erative advantage but also resistance to the glucocorticoid receptor recruitment to gluco- genotoxic stress induced by chemotherapy corticoid responsive genes and ultimately [45]. decreased glucocorticoid signaling caused by increased levels of NCoR and HDAC3. The WES and array-based comparative genomic resistance is specific for glucocorticoid ago- hybridization (aCGH) have been proven to be nists. Treatment with the HDAC inhibitor SAHA effective tools in identifying small genomic restores sensitivity to prednisolone in TBL1XR1- alterations in formalin-fixed paraffin-embedded depleted cells [22]. (FFPE) specimens. Using WES analysis, recurrent mutations of TBL1XR1 have been identi- A novel t(3;17)(q26.32;q21) translocation has fied in 19% of primary central nervous system recently been reported in three patients with lymphoma (PCNSL) cases [48, 49]. The muta- acute promyelocytic leukemia (APL). The rear- tions are clustered in three main regions: LisH rangement results in a fusion product between domain, F-box like domain and the C-terminus. exons1-3 of TBL1XR1 gene and exons 6-8 of Interestingly, one mutation at the C-terminus RAR gene. The TBL1XR1/RARα protein is pre- affects the potential phosphorylation site. dominantly localized in the nucleus and can MYD88 mutations are also frequent in the form homodimers or heterodimers with retinoid same patient group. Moreover, a novel mis- X receptor α. The fusion protein can act as tran- sense mutation in TBL1XR1 (T229R) was iden- scriptional activator in the presence of ligand, tified in a patient with Sezary syndrome, which but the transactivity is much weaker than converts a neutral to a hydrophilic amino acid RARα. The TBLR1-RARα product exhibits dimin- [50]. Since MYD88 and TBL1XR1 both are ished transcriptional activity as a result of the involved in NF-κB signaling pathway, it is possi- recruitment of more transcriptional corepres- ble that TBL1XR1 mutations lead to aberrant sors compared with RARα. In the presence of activation of NF-κB pathway and subsequent pharmacologic doses of ATRA, TBLR1-RARα lymphomagenesis. In one study, focal deletions could be degraded, and its homodimerization affecting sole TBL1XR1 gene are identified in was abrogated [55]. three out of nine PCNSL cases by aCGH analysis [51]. Similar genomic alterations are also Therapeutic potentials of targeting TBL1XR1- reported in a small subset of de novo DLBCL related pathways cases. Like the B-lymphoblastic leukemia with deletions of TBL1XR1, these patients may Disruption of interactions between TBL1XR1 develop resistance to steroid therapy due to and NCoR has been shown to inhibit gene loss of normal functions. repression by unliganded NRs [3]. Overexpre- ssion of the TBL1XR1-interacting domain of TBL1XR1 abnormalities in acute leukemias NCoR (DN-RD1) in frog oocytes can disrupt the interaction between endogeneous NCoR and Focal deletions of TBL1XR1 have been identi- TBL1XR1 and reverse the repression by unli- fied in 3 to 10% of acute lymphoblastic leuke- ganded RAR/RXR [4]. Knockdown of TBL1X or mia (ALL) patients [52]. The ETV6-RUNX1 TBL1XR1 by shRNA in cell lines can block the fusion is the molecular consequence of the binding of β-catenin to TCF4 and repress the t(12;21)(p13;q22), which is seen in approxi- transcription of WNT-β-catenin target genes, mately 25% of children with B-ALL. Focal dele- leading to inhibition of cell proliferation [8]. tions of TBL1XR1 have been observed in 15% These research findings lay the foundation for of these cases and appear to be exclusive for development of therapies targeting these plat- this subtype. A q-PCR analysis showed that the forms. A recent pre-clinical study, testing

19 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1 effects of BC2059 (β-Cat Pharmaceuticals), a Address correspondence to: Dr. Xinmin Zhang, small anthraquinone oxime-analog molecule on Department of Pathology and Laboratory Medicine, the growth of AML stem and blast progenitor Hofstra North Shore-LIJ School of Medicine, 6 Ohio cells (BPCs), provided promising results. Drive, Suite 202, Lake Success, NY 11042. Tel: 516 Treatment with BC2059 disrupts the binding of 304 7242; Fax: 516 304 7270; E-mail: xzhang2@ β-catenin to TBL1X and promotes proteasomal nshs.edu degradation of β-catenin, inhibiting the expression of the genes of Wnt/β catennin pathway References both in the cultured cell lines and in primary AML BPCs. It also shows dose dependent inhi- [1] Zhang X, Dormady SP and Basch RS. Identifi- cation of four human cDNAs that are differen- bition of growth and induces apoptosis of cul- + tially expressed by early hematopoietic progen- tured and CD34 pAML BPCs expressing FLT3- itors. Exp Hematol 2000; 28: 1286-1296. + ITD, but not of normal CD34 bone marrow [2] Zhang J, Kalkum M, Chait BT and Roeder RG. progenitor cells. BC2059 enhances cell death The N-CoR-HDAC3 nuclear receptor corepres- induced by transient knockdown of TBL1X or sor complex inhibits the JNK pathway through β-catenin in MOLM13 cells and induces apop- the integral subunit GPS2. Mol Cell 2002; 9: tosis in MOLM13-TKIR cells (a FLT3 antagonist- 611-623. resistant cell line). More importantly, BC2059 [3] Yoon HG, Chan DW, Huang ZQ, Li J, Fondell JD, treatment (by IV injection) exerts potent in vivo Qin J and Wong J. Purification and functional anti-AML activity and significantly improved the characterization of the human N-CoR complex: survival of immune depleted mice engrafted the roles of HDAC3, TBL1 and TBLR1. EMBO J with cultured and patient-derived pAML BPCs. 2003; 22: 1336-1346. [4] Tomita A, Buchholz DR and Shi YB. Recruit- Furthermore, BC2059 and FLT3-antagonist ment of N-CoR/SMRT-TBLR1 corepressor com- quizartinib or ponatinib synergistically induces plex by unliganded thyroid hormone receptor apoptosis of the FLT3-ITD expressing cultured for gene repression during frog development. cells (MOLM13 and MV4-11) and primary AML Mol Cell Biol 2004; 24: 3337-3346. BPCs but not of normal CD34+ progenitor cells. [5] Tomita A, Buchholz DR, Obata K and Shi YB. Collectively, these findings support that the tar- Fusion protein of retinoic acid receptor alpha geted therapy is a promising approach in treat- with promyelocytic leukemia protein or promy- ing AML [56]. elocytic leukemia zinc finger protein recruits N-CoR-TBLR1 corepressor complex to repress Summary transcription in vivo. J Biol Chem 2003; 278: 30788-30795. TBL1XR1 is an evolutionarily conserved protein [6] Perissi V, Aggarwal A, Glass CK, Rose DW and that shares high structural and functional simi- Rosenfeld MG. A corepressor/coactivator ex- larities from yeast to human. Three human change complex required for transcriptional homologues have been identified. TBL1XR1 is activation by nuclear receptors and other regu- an intrinsic component of the SMRT/NCoR lated transcription factors. Cell 2004; 116: 511-526. corepressor complexes, and it is also required [7] Perissi V, Scafoglio C, Zhang J, Ohgi KA, Rose for transcriptional activation by NRs and other DW, Glass CK and Rosenfeld MG. TBL1 and regulated TFs. It is important for the activation TBLR1 phosphorylation on regulated gene pro- of multiple intracellular signaling pathways, moters overcomes dual CtBP and NCoR/SMRT such as Wnt-β-catenin, NF-κB, and Notch. It is transcriptional repression checkpoints. Mol preferentially expressed in human hematopoi- Cell 2008; 29: 755-766. etic stem cells and may be critical for the main- [8] Li J and Wang CY. TBL1-TBLR1 and beta- tenance of stem cells. Germline mutations in catenin recruit each other to Wnt target-gene TBL1XR1 or recurrent mutations are associat- promoter for transcription activation and onco- ed with intellectual disability. Dysregulation of genesis. Nat Cell Biol 2008; 10: 160-169. TBL1XR1 has been observed in a variety of [9] Choi HK, Choi KC, Yoo JY, Song M, Ko SJ, Kim neoplastic conditions. TBL1XR1 appears to be CH, Ahn JH, Chun KH, Yook JI and Yoon HG. Reversible SUMOylation of TBL1-TBLR1 regu- multifunctional and its functions are cell type- lates beta-catenin-mediated Wnt signaling. and context- dependent. However, its exact Mol Cell 2011; 43: 203-216. functions are still not clear. A recent pre-clinical [10] Hoberg JE, Yeung F and Mayo MW. SMRT dere- study shed light on the therapeutic potential of pression by the IkappaB kinase alpha: a pre- targeting TBL1XR1-related pathways in cancer requisite to NF-kappaB transcription and sur- treatment. vival. Mol Cell 2004; 16: 245-255.

20 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1

[11] Pons L, Cordier MP, Labalme A, Till M, Louvrier [20] Liu L, Lin C, Liang W, Wu S, Liu A, Wu J, Zhang C, Schluth-Bolard C, Lesca G, Edery P and San- X, Ren P, Li M and Song L. TBL1XR1 promotes laville D. A new syndrome of intellectual dis- lymphangiogenesis and lymphatic metastasis ability with dysmorphism due to TBL1XR1 dele- in esophageal squamous cell carcinoma. Gut tion. Am J Med Genet A 2015; 167A: 164-168. 2015; 64: 26-36. [12] Tabet AC, Leroy C, Dupont C, Serrano E, Her- [21] Daniels G, Li Y, Gellert LL, Zhou A, Melamed J, nandez K, Gallard J, Pouvreau N, Gadisseux JF, Wu X, Zhang X, Zhang D, Meruelo D, Logan SK, Benzacken B and Verloes A. De novo deletion Basch R and Lee P. TBLR1 as an androgen re- of TBL1XR1 in a child with non-specific devel- ceptor (AR) coactivator selectively activates AR opmental delay supports its implication in in- target genes to inhibit prostate cancer growth. tellectual disability. Am J Med Genet A 2014; Endocr Relat Cancer 2014; 21: 127-142. 164A: 2335-2337. [22] Jones CL, Bhatla T, Blum R, Wang J, Paugh SW, [13] Saitsu H, Tohyama J, Walsh T, Kato M, Ko- Wen X, Bourgeois W, Bitterman DS, Raetz EA, bayashi Y, Lee M, Tsurusaki Y, Miyake N, Goto Morrison DJ, Teachey DT, Evans WE, Garabedi- Y, Nishino I, Ohtake A, King MC and Matsumo- an MJ and Carroll WL. Loss of TBL1XR1 dis- to N. A girl with West syndrome and autistic rupts glucocorticoid receptor recruitment to features harboring a de novo TBL1XR1 muta- chromatin and results in glucocorticoid resis- tion. J Hum Genet 2014; 59: 581-583. tance in a B-lymphoblastic leukemia model. J [14] O’Roak BJ, Vives L, Fu W, Egertson JD, Stan- Biol Chem 2014; 289: 20502-20515. away IB, Phelps IG, Carvill G, Kumar A, Lee C, [23] Zhang XM, Chang Q, Zeng L, Gu J, Brown S and Ankenman K, Munson J, Hiatt JB, Turner EH, Basch RS. TBLR1 regulates the expression of Levy R, O’Day DR, Krumm N, Coe BP, Martin nuclear hormone receptor co-repressors. BMC BK, Borenstein E, Nickerson DA, Mefford HC, Cell Biol 2006; 7: 31. Doherty D, Akey JM, Bernier R, Eichler EE and [24] Bassi MT, Ramesar RS, Caciotti B, Winship IM, Shendure J. Multiplex targeted sequencing De Grandi A, Riboni M, Townes PL, Beighton P, identifies recurrently mutated genes in autism Ballabio A and Borsani G. X-linked late-onset spectrum disorders. Science 2012; 338: sensorineural deafness caused by a deletion 1619-1622. involving OA1 and a novel gene containing WD- [15] Liu Y, Sun W, Zhang K, Zheng H, Ma Y, Lin D, 40 repeats. Am J Hum Genet 1999; 64: 1604- Zhang X, Feng L, Lei W, Zhang Z, Guo S, Han N, 1616. Tong W, Feng X, Gao Y and Cheng S. Identifica- [25] Yan HT, Shinka T, Kinoshita K, Sato Y, Umeno tion of genes differentially expressed in human M, Chen G, Tsuji K, Unemi Y, Yang XJ, Iwamoto primary lung squamous cell carcinoma. Lung T and Nakahori Y. Molecular analysis of TBL1Y, Cancer 2007; 56: 307-317. a Y-linked homologue of TBL1X related with X- [16] Kadota M, Sato M, Duncan B, Ooshima A, Yang linked late-onset sensorineural deafness. J HH, Diaz-Meyer N, Gere S, Kageyama S, Fu- Hum Genet 2005; 50: 175-181. kuoka J, Nagata T, Tsukada K, Dunn BK, Wake- [26] Dong X, Tsuda L, Zavitz KH, Lin M, Li S, Carthew field LM and Lee MP. Identification of novel RW and Zipursky SL. ebi regulates epidermal gene amplifications in breast cancer and coex- growth factor receptor signaling pathways in istence of gene amplification with an activating Drosophila. Genes Dev 1999; 13: 954-965. mutation of PIK3CA. Cancer Res 2009; 69: [27] Yoon HG, Choi Y, Cole PA and Wong J. Reading 7357-7365. and function of a histone code involved in tar- [17] Li X, Liang W, Liu J, Lin C, Wu S, Song L and geting corepressor complexes for repression. Yuan Z. Transducin (beta)-like 1 X-linked recep- Mol Cell Biol 2005; 25: 324-335. tor 1 promotes proliferation and tumorigenicity [28] Gerlitz G, Darhin E, Giorgio G, Franco B and in human breast cancer via activation of beta- Reiner O. Novel functional features of the Lis-H catenin signaling. Breast Cancer Res 2014; domain: role in protein dimerization, half-life 16: 465. and cellular localization. Cell Cycle 2005; 4: [18] Wang J, Ou J, Guo Y, Dai T, Li X, Liu J, Xia M, Liu 1632-1640. L and He M. TBLR1 is a novel prognostic mark- [29] Cerna D and Wilson DK. The structure of Sif2p, er and promotes epithelial-mesenchymal tran- a WD repeat protein functioning in the SET3 sition in cervical cancer. Br J Cancer 2014; corepressor complex. J Mol Biol 2005; 351: 111: 112-124. 923-935. [19] Chen SP, Yang Q, Wang CJ, Zhang LJ, Fang Y, [30] Huang W, Jin Y, Yuan Y, Bai C, Wu Y, Zhu H and Lei FY, Wu S, Song LB, Guo X and Guo L. Trans- Lu S. Validation and target gene screening of ducin beta-like 1 X-linked receptor 1 suppress- hsa-miR-205 in lung squamous cell carcino- es cisplatin sensitivity in Nasopharyngeal Car- ma. Chin Med J (Engl) 2014; 127: 272-278. cinoma via activation of NF-kappaB pathway. [31] Guenther MG, Lane WS, Fischle W, Verdin E, Mol Cancer 2014; 13: 195. Lazar MA and Shiekhattar R. A core SMRT co-

21 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1

repressor complex containing HDAC3 and C, Chowdhury SA, Schwartz R, Schaffer AA, TBL1, a WD40-repeat protein linked to deaf- Paris PL and Ried T. Single-cell genetic analy- ness. Genes Dev 2000; 14: 1048-1057. sis reveals insights into clonal development of [32] Choi HK, Choi KC, Kang HB, Kim HC, Lee YH, prostate cancers and indicates loss of PTEN as Haam S, Park HG and Yoon HG. Function of a marker of poor prognosis. Am J Pathol 2014; multiple Lis-Homology domain/WD-40 repeat- 184: 2671-2686. containing proteins in feed-forward transcrip- [44] Stransky N, Cerami E, Schalm S, Kim JL and tional repression by silencing mediator for reti- Lengauer C. The landscape of kinase fusions noic and thyroid receptor/nuclear receptor in cancer. Nat Commun 2014; 5: 4846. corepressor complexes. Mol Endocrinol 2008; [45] Scott DW, Mungall KL, Ben-Neriah S, Rogic S, 22: 1093-1104. Morin RD, Slack GW, Tan KL, Chan FC, Lim RS, [33] Huang W, Ghisletti S, Perissi V, Rosenfeld MG Connors JM, Marra MA, Mungall AJ, Steidl C and Glass CK. Transcriptional integration of and Gascoyne RD. TBL1XR1/TP63: a novel re- TLR2 and TLR4 signaling at the NCoR dere- current gene fusion in B-cell non-Hodgkin lym- pression checkpoint. Mol Cell 2009; 35: 48- phoma. Blood 2012; 119: 4949-4952. 57. [46] Vasmatzis G, Johnson SH, Knudson RA, Ketter- [34] Cadigan KM. Wnt/beta-catenin signaling: turn- ling RP, Braggio E, Fonseca R, Viswanatha DS, ing the switch. Dev Cell 2008; 14: 322-323. Law ME, Kip NS, Ozsan N, Grebe SK, Frederick [35] Verstrepen L and Beyaert R. Receptor proximal LA, Eckloff BW, Thompson EA, Kadin ME, Milo- kinases in NF-kappaB signaling as potential sevic D, Porcher JC, Asmann YW, Smith DI, therapeutic targets in cancer and inflamma- Kovtun IV, Ansell SM, Dogan A and Feldman tion. Biochem Pharmacol 2014; 92: 519-529. AL. Genome-wide analysis reveals recurrent [36] Keutgens A, Shostak K, Close P, Zhang X, Hen- structural abnormalities of TP63 and other nuy B, Aussems M, Chapelle JP, Viatour P, Go- p53-related genes in peripheral T-cell lympho- thot A, Fillet M and Chariot A. The repressing mas. Blood 2012; 120: 2280-2289. function of the oncoprotein BCL-3 requires [47] Chavan RN, Bridges AG, Knudson RA, Ketter- CtBP, while its polyubiquitination and degrada- ling RP, Comfere N, Wada DA, Torres-Cabala C, tion involve the E3 ligase TBLR1. Mol Cell Biol DiCaudo DJ, Vasmatzis G, Pittelkow MR and 2010; 30: 4006-4021. Feldman AL. Somatic rearrangement of the [37] Ishii S, Kurasawa Y, Wong J and Yu-Lee LY. His- TP63 gene preceding development of mycosis tone deacetylase 3 localizes to the mitotic fungoides with aggressive clinical course. spindle and is required for kinetochore-micro- Blood Cancer J 2014; 4: e253. tubule attachment. Proc Natl Acad Sci U S A [48] Gonzalez-Aguilar A, Idbaih A, Boisselier B, Hab- 2008; 105: 4179-4184. bita N, Rossetto M, Laurenge A, Bruno A, Jou- [38] Terstappen LW, Huang S, Safford M, Lansdorp vet A, Polivka M, Adam C, Figarella-Branger D, PM and Loken MR. Sequential generations of Miquel C, Vital A, Ghesquieres H, Gressin R, hematopoietic colonies derived from single Delwail V, Taillandier L, Chinot O, Soubeyran P, nonlineage-committed CD34+CD38- progeni- Gyan E, Choquet S, Houillier C, Soussain C, tor cells. Blood 1991; 77: 1218-1227. Tanguy ML, Marie Y, Mokhtari K and Hoang- [39] Novelli EM, Ramirez M and Civin CI. Biology of Xuan K. Recurrent mutations of MYD88 and CD34+CD38- cells in lymphohematopoiesis. TBL1XR1 in primary central nervous system Leuk Lymphoma 1998; 31: 285-293. lymphomas. Clin Cancer Res 2012; 18: 5203- [40] Lim YM, Hayashi S and Tsuda L. Ebi/AP-1 sup- 5211. presses pro-apoptotic genes expression and [49] Bruno A, Boisselier B, Labreche K, Marie Y, Po- permits long-term survival of Drosophila sen- livka M, Jouvet A, Adam C, Figarella-Branger D, sory neurons. PLoS One 2012; 7: e37028. Miquel C, Eimer S, Houillier C, Soussain C, [41] Mandal C, Park JH, Choi MR, Kim SH, Badejo Mokhtari K, Daveau R and Hoang-Xuan K. Mu- AC, Chai JC, Lee YS, Jung KH and Chai YG. Tran- tational analysis of primary central nervous scriptomic study of mouse embryonic neural system lymphoma. Oncotarget 2014; 5: 5065- stem cell differentiation under ethanol treat- 5075. ment. Mol Biol Rep 2015; [Epub ahead of [50] Andersson E, Eldfors S, Edgren H, Ellonen P, print]. Vakeva L, Ranki A and Mustjoki S. Novel [42] Daniels G, Jha R, Shen Y, Logan SK and Lee P. TBL1XR1, EPHA7 and SLFN12 mutations in a Androgen receptor coactivators that inhibit Sezary syndrome patient discovered by whole prostate cancer growth. Am J Clin Exp Urol exome sequencing. Exp Dermatol 2014; 23: 2014; 2: 62-70. 366-368. [43] Heselmeyer-Haddad KM, Berroa Garcia LY, [51] Braggio E, McPhail ER, Macon W, Lopes MB, Bradley A, Hernandez L, Hu Y, Habermann JK, Schiff D, Law M, Fink S, Sprau D, Giannini C, Dumke C, Thorns C, Perner S, Pestova E, Burke Dogan A, Fonseca R and O’Neill BP. Primary

22 Am J Clin Exp Urol 2015;3(1):13-23 The role of TBL1XR1

central nervous system lymphomas: a valida- [54] Olsson L, Castor A, Behrendtz M, Biloglav A, tion study of array-based comparative genom- Forestier E, Paulsson K and Johansson B. De- ic hybridization in formalin-fixed paraffin-em- letions of IKZF1 and SPRED1 are associated bedded tumor specimens. Clin Cancer Res with poor prognosis in a population-based se- 2011; 17: 4245-4253. ries of pediatric B-cell precursor acute lympho- [52] Parker H, An Q, Barber K, Case M, Davies T, blastic leukemia diagnosed between 1992 Konn Z, Stewart A, Wright S, Griffiths M, Ross and 2011. Leukemia 2014; 28: 302-310. FM, Moorman AV, Hall AG, Irving JA, Harrison [55] Chen Y, Li S, Zhou C, Li C, Ru K, Rao Q, Xing H, CJ and Strefford JC. The complex genomic pro- Tian Z, Tang K, Mi Y, Wang B, Wang M and file of ETV6-RUNX1 positive acute lymphoblas- Wang J. TBLR1 fuses to retinoid acid receptor tic leukemia highlights a recurrent deletion of alpha in a variant t(3;17)(q26;q21) transloca- TBL1XR1. Genes Chromosomes Cancer 2008; tion of acute promyelocytic leukemia. Blood 47: 1118-1125. 2014; 124: 936-945. [53] Zhang J, Mullighan CG, Harvey RC, Wu G, Chen [56] Fiskus W, Sharma S, Saha S, Shah B, Devaraj X, Edmonson M, Buetow KH, Carroll WL, Chen SG, Sun B, Horrigan S, Leveque C, Zu Y, Iyer S IM, Devidas M, Gerhard DS, Loh ML, Reaman and Bhalla KN. Pre-clinical efficacy of com- GH, Relling MV, Camitta BM, Bowman WP, bined therapy with novel beta-catenin antago- Smith MA, Willman CL, Downing JR and Hun- nist BC2059 and histone deacetylase inhibitor ger SP. Key pathways are frequently mutated in against AML cells. Leukemia 2014; [Epub high-risk childhood acute lymphoblastic leuke- ahead of print]. mia: a report from the Children’s Oncology Group. Blood 2011; 118: 3080-3087.

23 Am J Clin Exp Urol 2015;3(1):13-23