The Role of TCL1 in Human T-Cell Leukemia

The role of TCL1 in human T-cell leukemia

Yuri Pekarsky1, Cora Hallas1 and Carlo M Croce*,1

1Kimmel Cancer Center, Thomas Jeerson University, 233 South 10th Street Philadelphia, Pennsylvania, PA 19107, USA

The TCL1 locus on human chromosome 14q32.1 is human c-myc gene activated by an immunoglobulin activated in T-cell leukemias by translocations and enhancer developed B-cell lymphoma (Schmidt et al., inversions that juxtapose it to regulatory elements of 1988). Therefore deregulation of the c-myc oncogene is T-cell receptor genes. We isolated and characterized four the causing event in the development of Burkitt's genes at this locus, TCL1 and TCL1b (T-cell leukemia/ lymphomas. Another important example for the critical lymphoma 1 and 1b), and TNG1 and TNG2 (TCL role of chromosomal translocations in hematopoietic neighboring genes 1 and 2) all of which are over- malignancies are rearrangements at involving the ALL1 expressed following rearrangements involving 14q32.1. gene at 11q23 (reviewed in Croce, 1999). ALL1 can be TCL1 and TCL1b show 60% similarity and are fused to many dierent genes and even to itself in a represented in the mouse by a cluster of six homologous variety of acute leukemias (Cimino et al., 1991; Gu et genes. In humans TCL1 and TCL1b show similar al., 1992; Schichman et al., 1994). The critical role of expression patterns: They are expressed mainly in ALL1 in the pathogenesis of ALL was con®rmed by CD4-/CD8- immature T-cells, pre B-cells and virgin B- the study of ALL1 transgenic mouse models showing cells. Expression decreases signi®cantly at more mature the development of acute leukemias (Corral et al., stages of B-cell development. Activation of TCL1 and/or 1996). Since ALL1 has so many dierent fusion TCL1b in mature T-cells causes T-cell leukemia in partners it is likely that the oncogenic event in this humans. The oncogenic nature of TCL1 was con®rmed rearrangement is the loss of function of this gene. by the analysis of a transgenic mouse model. Functional analysis of Tcl1 revealed its involvement in a PI3-kinase dependent Akt (PKB) pro-survival pathway through its Chromosomal rearrangements and genes at 14q32.1 interaction with the Akt kinase which increases Akt's enzymatic activity and promotes translocation of Akt to Rearrangements at the TCL1 (T-cell leukemia/lympho- the nucleus. Oncogene (2001) 20, 5638 ± 5643. ma 1) locus are associated with T-cell leukemias of the mature phenotype such as T-cell prolymphocytic Keywords: 14q32.1; TCLI; TCLIb; Akt; T-cell leukemia leukemia (T-PLL) (Taylor et al., 1996), adult T-cell leukemia (ATL) (Narducci et al., 1997) and with chronic T-cell leukemias that develop in patients with the immunode®ciency syndrome ataxia telangiectasia Most human leukemias and lymphomas carry chro- (AT) (Brito-Babapulle and Catovsky, 1991). Most mosomal rearrangements, predominantly transloca- often, the TCL1 locus at chromosome 14q32.1 tions (Croce, 1987; Rabbitts, 1991). These rearranges with the TCR (T-cell receptor) a/d locus rearrangements initiate a multistep process that results at chromosome 14q11 (Figure 1) (Russo et al., 1989; in malignant transformation, although they may be Virgilio et al., 1993). Since both loci reside on the same also involved in tumor progression (Pegoraro et al., chromosome, these rearrangements can either be 1984). The role of chromosomal translocations in the reciprocal translocations t(14;14)(q11;q32) or inver- pathogenesis of human leukemias and lymphomas was sions inv(14)(q11;q32). In the case of the translocation ®rst demonstrated in the studies of Burkitt's lympho- t(14;14)(q11;q32) the abnormal chromosome 14 con- mas, a high grade childhood malignancy of B-cells tains two copies of the TCL1 locus: one normal copy (Dalla-Favera et al., 1982). The rearrangements in in the distal part of the chromosome and one Burkitt's lymphomas juxtapose the c-myc oncogene at rearranged TCL1 copy juxtaposed to the J segment 8q24 to one of the immunoglobulin loci on either 2p11, of the TCRa/d receptor (Figure 1). On the chromo- 14q32.3 or 22q11 (Ericson et al., 1982). This results in some 14 carrying the inversion inv(14)(q11;q32) the the transcriptional activation of the c-myc oncogene by rearranged TCL1 locus is also linked to a J/D segment the enhancer elements of the immunoglobulin loci (ar- of the TCRa receptor, although in this case the Rushdi et al., 1983). Transgenic mice bearing the orientation of the TCL1 locus is opposite to that of the translocation t(14;14)(q11;q32) (Figure 1). The activation of TCL1 by both types of rearrangements suggests that the TCRa enhancer may activate the *Correspondence: CM Croce, Kimmel Cancer Institute, 233 South 10th Street, BLSB Room 1050, Philadelphia, Pennsylvania 19107, locus either in 3' or in 5' orientation. It is also USA; E-mail: [email protected] important to note, that rearrangements of the TCL1 The role of TCL1 in human T-cell leukemia Y Pekarsky et al 5639

Figure 1 TCL1 locus rearrangements in human T-cell leukemias: inv(14)(q11;q32.1) and t(14;14)(q11;q32.1)

locus have been observed in T-cell clonal expansions found three additional genes: TNG1 (TCL1 neighbor- occurring in patients with AT before the onset of frank ing gene 1), TNG2 and TCL1b (Hallas et al., 1999; leukemia (Narducci et al., 1995). Pekarsky et al., 1999). Expression analysis of these Since the TCL1 locus at 14q32.1 is frequently genes showed a complex alternative splicing pattern involved in chromosomal rearrangements in T-cell including fusion transcripts between the genes. TNG1 leukemias we speculated that an oncogene important and TNG2 encode proteins with no signi®cant for the induction and/or development of T-cell homology to any known proteins or protein motifs leukemias is located in this region (Croce et al., (Hallas et al., 1999). TCL1b is located only 15 kb 1985). To isolate this gene(s) we ®rst constructed a centromeric of TCL1 with the opposite direction of P1 contig covering 14q32.1 and mapped several transcription (Figure 2). Interestingly TCL1b, encodes 14q32.1 breakpoints within this region (Virgilio et al., a 14 kD protein of 128 amino acids, which shows 60% 1993). Genomic analysis of our contig revealed that an similarity to TCL1, and contains an insertion of 14 approximately 120 kb DNA segment is located amino acids when compared to TCL1 (Pekarsky et al., between two clusters of breakpoints observed in 1999). various leukemic samples and cell lines (Figure 2). To develop mouse models for the 14q32.1 oncogenic Further analysis of this 120 kb region resulted in the locus we also characterized the murine counterpart of discovery of the TCL1 gene formed by four exons with that region. EST analysis of murine Tcl1 and Tcl1b a coding sequence of 114 amino acids and a 3' orthologs suggested the existence of several Tcl1b genes untranslated region of about 800 nucleotides (Virgilio in the mouse. Sequence analysis of a BAC clone et al., 1994, Figure 2). The Tcl1 protein shares a 41% containing the murine Tcl1 locus revealed the existence amino acid sequence identity with the peptide encoded of ®ve dierent Tcl1b homologs adjacent to the murine by one of the open reading frames of the MTCP1 gene Tcl1 gene (Hallas et al., 1999). All six genes span an located at Xq28 and activated in rare cases of mature 80 kb DNA segment on the murine chromosome 12 T-cell leukemia with a t(X;14)(q28;q11) translocation (Figure 3). Expression analysis revealed mRNA for all (Stern et al., 1993; Madani et al., 1996). ®ve Tcl1b genes (Tcl1b1 ± Tcl1b5) encoding similar but Additional studies have shown that TCL1 becomes distinct proteins (Hallas et al., 1999). activated as a consequence of the TCL1 locus rearrangements and that its activation is the ®rst step Expression analysis of the TCL1 locus in normal tissues in T-cell neoplasia (Virgilio et al., 1994, 1998). and hematopoietic malignancies However, some cases of T-cell malignancies with abnormalities, such as gene ampli®cation at 14q32.1, To determine the relevance of all the genes at the did not show activation of TCL1 expression (Ariyama TCL1 locus in T-cell leukemogenesis we proceeded to et al., 1999; Sakashita et al., 1998; Takizawa et al., investigate the expression analysis of these genes. Since 1998), suggesting that perhaps an additional oncogene its discovery, the expression of TCL1 in normal and may be located in 14q32.1 (Takizawa et al., 1998). In tumor tissues has been studied in great detail. The order to look for this putative additional oncogene we protein can be found in most stages of B-cell further analysed the 14q32.1 breakpoint region and development including pre-B-cells, surface lgM expres-

Oncogene The role of TCL1 in human T-cell leukemia Y Pekarsky et al 5640

Figure 2 Genomic organization of human TCL1 locus at 14q32.1

Figure 3 Genomic organization of mouse Tcl1 locus

sing virgin B-cells, mantle cells and germinal center B- cells (Narducci et al., 2000; Takizawa et al., 1998). It is down regulated only at later stages of B-cell development, i.e. plasma cells. In T-cells, however, TCL1 is only expressed at the very early CD47/CD87 double negative stage (Virgilio et al., 1994; Narducci et al., 2000). More mature T-cells do not normally show any TCL1 expression (Figure 4). Other non-lymphatic Figure 4 Activation of TCL1 expression in SupT11 T-cell tissues or cell lines tested also do not express TCL1 leukemia cell line. Northern blot analysis was carried out using with the exception of ovaries and ovarian tumors RNAs of the following T-cell lines: Molt3 (lane 1), Molt4 (lane 2), (Virgilio et al., 1994). In contrast to this normal Jurket (lane 3) and SupT11 (lane 4) expression pattern, we showed that the TCL1 oncogene is activated by chromosomal translocations in the majority of T-PLLs (Virgilio et al., 1994) and this ®nding TCL1, is also activated in the SupT11 leukemias arising in patients with ataxia telangiectasia leukemic T-cell line, that carries a t(14 : 14)(q11;q32) (AT) (Thick et al., 1996). TCL1 is also overexpressed chromosomal translocation (Virgilio et al., 1994, in adult T-cell leukemias (ATL) when compared to Figure 4). Some of the breakpoints that are seen in normal T-cells (Narducci et al., 1997). Consistent with these types of leukemias are shown in Figure 2.

Oncogene The role of TCL1 in human T-cell leukemia Y Pekarsky et al 5641 The other three genes in this locus, TCL1b, TNG1 genesis. Among the proteins we considered for and TNG2, show an expression pattern very similar to investigation was the protein kinase Akt/PKB. Akt is that of TCL1. Most importantly, they are not the human homolog of v-akt, a gene isolated from the expressed in most normal T-cells, but activated in the retrovirus AKT8, which causes T-cell lymphomas in SupT11 cell line and in samples from T-PLL patients mice (Staal et al., 1977). Akt is a key player in the as shown in Figure 3 (Hallas et al., 1999). transduction of anti-apoptotic and proliferative signals Interestingly, the expression pattern of the genes of in T-cells (reviewed in Chan et al., 1999). Recent the murine Tcl1 locus is signi®cantly dierent. studies have shown that Akt phosphorylates and Expression of murine Tcl1 and Tcl1b genes was not regulates a variety of key targets important for cell detected in any of the adult mouse tissues analysed, survival and proliferation like Bad (Mok et al., 1999), including lymphoid tissues, although a detailed study Raf (Zimmermann and Moelling, 1999), and IKKa of the expression in murine lymphogenesis is yet to be (Ozes et al., 1999). Introduction of a constitutively carried out. The only signi®cant expression of these activated Akt under the control of the proximal lck genes was found in oocytes and at the earliest stages of promoter causes T-cell lymphomas in mice. Akt mouse embryogenesis (Hallas et al., 1999). contains a pleckstrin homology domain which is thought to mediate protein ± protein interactions, and a kinase domain. The protein kinase can be activated TCL1 is a bona fide oncogene by insulin and various other growth and survival Activation of TCL1 in T-cell leukemia can be factors (reviewed in Chan et al., 1999). explained through two dierent mechanisms: TCL1 To explore the possibility that Tcl1 and Akt function expression is causative in T-cell leukemia or it is a non- in the same pathway, we ®rst investigated whether the essential secondary event. To prove that TCL1 is a two proteins interact physically. Co-immunoprecipita- bona ®de oncogene involved in tumor initiation we tion experiments demonstrated that Akt1 forms introduced the human TCL1 cDNA under the control immune complexes with Tcl1. Investigation of the of the lck proximal promoter into fertilized mouse eggs other members of the two gene families (Tcl1b, Akt2, (Virgilio et al., 1998). These transgenic mice developed and Akt3) showed no signi®cant interaction between premalignant T-cell proliferations expressing TCL1 either of them as determined by immunoprecipitation cDNA starting at the age of 6 months. Older mice (Pekarsky et al., 2000). Another study has demon- (in average 15 month of age) developed mature T-cell strated co-immunoprecipitation of Akt1 and Mtcp1 leukemias. Interestingly, the leukemias in the trans- and interaction of Akt2 and Tcl1, Tcl1b, and Mtcp1 in genic mice were predominatly CD47/CD8+ in the more sensitive yeast two hybrid system (Laine et contrast to human leukemias with TCL1 involvement al., 2000). Studies of the eect of Tcl1 on Akt function which are mostly CD4+/CD87 (Virgilio et al., 1998). found that Tcl1 enhances the kinase activity of Akt With the aid of this mouse model we were able to (Pekarsky et al., 2000; Laine et al., 2000). The prove that TCL1 is an actual oncogene and that its activation of Akt by growth and survival factors deregulation initiates the process of malignant trans- involves a phosphatidylinositol 3-kinase (PI3-K)-de- formation. The introduction of another member of the pendent membrane translocation step that is attributed TCL1 gene family, MTCP1, under the control of the to the binding of the PH-domain to D3 phosphoinosi- CD2 promoter (another T-cell speci®c promoter) tides and a PDK-1 mediated phosphorylation step of resulted in the development of a similar type of Trp308 and Ser473 (Chan et al., 1999). A recent report leukemia in that transgenic model, although with a showed that Tcl1 promotes the oligomerization of Akt CD47/CD8+ phenotype (Gritti et al., 1998). Thus, and thereby enhances its kinase activity (Laine et al., deregulation of two members of the TCL1 gene family, 2000). The same study also claimed that Tcl1 enhances TCL1 and MTCP1, in T-cells causes the development the phosphorylation of Ser473 of Akt, although our of T-cell leukemias in transgenic animals at older ages results could not con®rm this ®nding. Therefore we similar to adult T-cell leukemias in humans. It will be believe that the interaction of Tcl1 and Akt1 causes a of considerable interest to determine whether TCL1b conformational change of Akt by oligomerization or transgenic mice also develop mature T-cell leukemia interaction with other proteins which increases the late in life and whether TCL1 and TCL1b may kinase activity of Akt. synergize to lead to an earlier onset of the disease. The intracellular localization of Akt is primarily cytoplasmic (Chan et al., 1999). Tcl1, on the other hand, is located in both the cytoplasm and the nucleus Functional aspects of Tcl1 (Pekarsky et al., 2000). Our two color immuno¯uores- Although several reports demonstrated the involvement cence experiments showed that co-expression of Akt1 of TCL1 in the pathogenesis of T-cell leukemias and and Tcl1 in the same cells leads to co-localization of that the activation of the gene is the causing event in both proteins in the nucleus and the cytoplasm. Co- the development of human T-cell malignancies, the expression of myristoylated Akt (con®ned to the way in which Tcl1 acts to achieve its oncogenic eect cytoplasm) and Tcl1 con®rmed this co-localization by was not known until recently. To identify the retaining Tcl1 in the cytoplasm (Pekarsky et al., 2000). molecular role of Tcl1 and interacting proteins we Thus, we and others demonstrated that Tcl1 interacts looked at other proteins involved in T-cell leukemo- with Akt1, enhances Akt1 kinase activity and promotes

Oncogene The role of TCL1 in human T-cell leukemia Y Pekarsky et al 5642 the nuclear translocation of Akt1. The enzymatic dierentiation, proliferation and apoptosis of hemato- activity of Akt is critical for its oncogenic function poietic cells. Activation of TCL1, one of the members (i.e. for phosphorylation and regulation of cell cycle of this family, is a crucial initial step in the regulatory molecules such as Bad, Raf, and IKKa), development of T-cell leukemias, as was proven in therefore the enhancement of this activity by Tcl1 the transgenic mouse model (Virgilio et al., 1998). represents one mechanism of Tcl1 oncogenic function. Nevertheless, other genetic changes are probably Since all reported targets of Akt are cytoplasmic our necessary for the pathogenesis of a full-blown ®nding that Tcl1 translocates Akt to the nucleus led us leukemia, since the mice develop a mature T-cell to believe that there is at least one nuclear target of leukemia late in life (Virgilio et al., 1998). Akt that is important for T-cell proliferation or death. On the other hand, TCL1 is not the only gene that Our results led us to search for such a T-cell speci®c can be activated by chromosomal aberrations involving nuclear target containing an Akt phosphorylation site. 14q32.1. TCL1b, TNG1,andTNG2 may also be The orphan nuclear receptor Nur77 (also known as involved in the pathogenesis of T-cell malignancies, NGFI-B or TR3) drew our attention: Nur77 is a and may be acting as oncogenes on their own or in critical molecule for apoptosis in T-cells and it has an concert with TCL1 or each other (Hallas et al., 1999; Akt phosphorylation site at Ser350 (Cheng et al., Pekarsky et al., 1999). Although the exact biological 1997). It is required for T-cell antigen receptor function of Tcl1 is still not clear, we were able to mediated apoptosis in immature thymocytes under- demonstrate its involvement in the enhancement of the going selection and it is induced in T-cell hybridomas PI3-K dependent anti-apoptotic function of Akt (Cheng et al., 1997). The transactivational activity of (Pekarsky et al., 2000). Tcl1 also transports Akt to Nur77 is mediated through a unique response element the nucleus. However, because Tcl1 has no nuclear (Davis et al., 1993). The phosphorylation of Ser350, localization signal, the exact mechanism of this located in the DNA-binding domain, was shown to phenomenon needs to be studied. The nuclear inhibit the DNA binding and transcriptional activity of translocation of Akt by Tcl1 hints to the existence of Nur77 in vitro (Hirata et al., 1993) and in vivo (Katagiri nuclear target(s) of Akt important for the survival and/ et al., 1997). Our experiments showed that Akt or apoptosis of T-cells. Additional experiments are interacts with and phosphorylates Nur77 at Ser350 in necessary to identify these target(s), since Nur77 turned a PI3-K dependent manner and thereby inhibits the out to be phosphorylated by Akt in the cytoplasm function of Nur77 as a proapoptotic transcription (Pekarsky et al., 2001). factor. Cell fractionation experiments revealed that The complete understanding of the molecular phosphorylation of Nur77 by Akt took place in the mechanisms utilized by the members of the TCL1 cytoplasm and that the rate of phosphorylation was oncogene family will provide invaluable tools toward not in¯uenced by the presence of Tcl1 (Pekarsky et al., the understanding of the molecular bases of T-cell 2001) indicating that Tcl1 levels do not aect Nur77 leukemia molecular bases and will lead to development activity. Nevertheless it is premature to conclude that of novel targeted therapeutic approaches to this disease Tcl1 is not involved in the regulation of Nur77 since and other tumors as well. we conducted our experiments in an overexpressed system in non-lymphoid cells.

Conclusions Acknowledgments The analysis of chromosomal translocations in human This work was supported by NIH grant # CA 81534 to T-cell malignancies resulted in the identi®cation of a CMC and Special Fellowship of Leukemia and Lymphoma family of genes that are important for the development, Society to Y Pekarsky.

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