Aberrant expression of the <i>LHX4</i> LIM‐homeobox gene caused by t(1;14)(q25;q32) in chronic myelogenous leukemia in biphenotypic blast crisis

Yamaguchi, Mitsuko; Yamamoto, Koh; Miura, Osamu

doi:10.1002/gcc.10283

Cited by 16 publications

(14 citation statements)

References 21 publications

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“…In cellular transformation assays, using Rat1 and NIH3T3 cell lines, the oncogenic activities of the LHX4 gene could not be defined (Kawamata et al, 2002), but aberrant expression of this gene was observed in the case of chronic myeloid leukemia in blast crisis and in the case of pre-B acute lymphoblastic leukemia. Both cases carried a t(1;14)(q25;q32) chromosome translocation, which The SSX C terminus interacts with LHX4 DRH de Bruijn et al resulted in juxtaposition of the respective LHX4 and IGH genes (Kawamata et al, 2002;Yamaguchi et al, 2003). The LHX4 gene was also found to be overexpressed in the pre-B acute lymphoblastic leukemia cell line MD930 (Yamaguchi et al, 2003).…”

Section: Discussionmentioning

confidence: 98%

“…The LHX4 gene was also found to be overexpressed in the pre-B acute lymphoblastic leukemia cell line MD930 (Yamaguchi et al, 2003). During normal development, the LHX4 gene is predominantly expressed in the central nervous system (Liu et al, 2002), and it was proposed that its overexpression may be associated with cellular proliferation and/or anti-apoptosis (Kawamata et al, 2002;Yamaguchi et al, 2003). Indeed, mouse knockout studies revealed that LHX4 deficiency leads to an increased apoptotic rate in Rathke's pouch, resulting in an impaired pituitary development reminiscent of human congenital pituitary hormone deficiency (CPHD; Sheng et al, 1997;Machinis et al, 2001;Raetzman et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Through yeast two-hybrid screening, using the synovial sarcoma-associated SSX1 C terminus as a bait, we isolated two cDNAs corresponding to the LHX4 protein, a transcription factor that is known to be involved in pituitary and motor neuron development (Sheng et al, 1997;Sharma et al, 1998;Machinis et al, 2001;Raetzman et al, 2002) and to be deregulated and/ or translocated in human chronic myeloid and acute lymphoblastic leukemias (Wu et al, 1996;Dong et al, 1997;Wu and Minden, 1997;Kawamata et al, 2002;Yamaguchi et al, 2003). In the yeast two-hybrid system, the LHX4 protein interacts equally well with the C terminus of all SSX proteins known to be involved in synovial sarcoma, that is SSX1, SSX2 and SSX4.…”

Section: Discussionmentioning

confidence: 99%

“…Both cases carried a t(1;14)(q25;q32) chromosome translocation, which The SSX C terminus interacts with LHX4 DRH de Bruijn et al resulted in juxtaposition of the respective LHX4 and IGH genes (Kawamata et al, 2002;Yamaguchi et al, 2003). The LHX4 gene was also found to be overexpressed in the pre-B acute lymphoblastic leukemia cell line MD930 (Yamaguchi et al, 2003). During normal development, the LHX4 gene is predominantly expressed in the central nervous system (Liu et al, 2002), and it was proposed that its overexpression may be associated with cellular proliferation and/or anti-apoptosis (Kawamata et al, 2002;Yamaguchi et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Our The SSX C terminus interacts with LHX4 DRH de Bruijn et al data indicate that the C terminus of the SSX1, SSX2 and SSX4 proteins interact in vivo with the LIM homeobox protein LHX4. This transcription factor was previously found to be deregulated and/or translocated in chronic and acute leukemias (Wu et al, 1996;Dong et al, 1997;Wu and Minden, 1997;Kawamata et al, 2002;Yamaguchi et al, 2003). The putative implications of these novel protein -protein interactions for the development of human synovial sarcomas and other SSX-positive tumors are discussed.…”

Section: Introductionmentioning

confidence: 87%

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The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

et al. 2007

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As a result of the synovial sarcoma-associated t(X;18) translocation, the SS18 gene on chromosome 18 is fused to either one of the three closely related SSX genes on the X chromosome. The SS18 protein is thought to act as a transcriptional co-activator, whereas the SSX proteins are thought to act as transcriptional corepressors. The main SSX-repression domain is located in its C terminus, a domain that is retained in the respective SS18-SSX fusion proteins. Both the SS18 and SSX proteins lack DNAbinding domains. Previously, we found that the SS18 and SS18-SSX fusion proteins may be tethered to DNA targets via the SS18-interacting protein AF10. Here, we set out to isolate proteins that interact with the SSX C-terminal repression domain using a yeast two-hybrid interaction trap. Of the positive clones isolated, two corresponded to the LIM homeobox protein LHX4, a DNA-binding protein that is involved in transcription regulation. An endogenous interaction was subsequently established in mammalian cells via colocalization and coimmunoprecipitation of the respective proteins. Interestingly, the LHX4 gene was previously found to be deregulated in various human leukemias. In addition, it was previously found that LIM homeobox proteins may bind to and activate the glycoprotein-a (CGA) promoter. Using LHX4 chromatin immunoprecipitation and CGApromoter assays, we found that endogenous LHX4 binds to the CGA promoter and that LHX4-mediated CGA activation is enhanced by the SS18-SSX protein, but not by the SSX protein. Taken together, we conclude that this novel protein -protein interaction may have direct consequences for the (de)regulation of SSX and/or SS18-SSX target genes and, thus, for the development of human synovial sarcomas.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

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The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

et al. 2007

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The (Epi)genetics of human synovial sarcoma

Bruijn

Nap

Kessel

2006

Genes Chromosomes & Cancer

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Human synovial sarcomas are aggressive soft tissue tumors with relatively high rates of recurrences and metastases. They display a variable response to common treatment protocols such as radiation and chemotherapy. For the development of novel diagnostic, prognostic, and therapeutic approaches, detailed information on the molecular mechanisms underlying the development of these tumors is of imperative importance. Fusion of the SS18 and (one of the) SSX genes is a molecular hallmark of human synovial sarcomas. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcription regulatory activities, likely through epigenetic mechanisms. The SS18 protein functions as a transcriptional coactivator and interacts directly with members of the epigenetic chromatin remodeling and modification machineries. In contrast, the SSX proteins function as transcriptional corepressors and are associated with several Polycomb group proteins. Since the domains involved in these apparently opposite transcription regulatory activities are retained in the SS18-SSX fusion proteins, we hypothesize that these fusion proteins function as "activator-repressors" of transcription. The implications of this model for human synovial sarcoma development and future treatment are discussed.

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Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1‐PBX1 fusion gene in a myoepithelioma

Brandal

Panagopoulos

Bjerkehagen

et al. 2008

Genes Chromosomes & Cancer

125

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Chromosome banding as well as molecular cytogenetic methods are of great help in the diagnosis of mesenchymal tumors. Myoepithelial neoplasms of soft tissue including myoepitheliomas, mixed tumors, and parachordomas are diagnoses that have been increasingly recognized the last few years. It is still debated which neoplasms should be included in these morphologically heterogeneous entities, and the boundaries between them are not clear-cut. The pathogenetic mechanisms behind myoepithelial tumors are unknown. Only five parachordomas and one mixed tumor have previously been karyotyped, and nothing is known about their molecular genetic characteristics. We present a mesenchymal tumor classified as a myoepithelioma that had a balanced translocation t(1;22)(q23;q12) as the sole karyotypic change. A novel EWSR1-PBX1 fusion gene consisting of exons 1-8 of the 5'-end of EWSR1 and exons 5-9 of the 3'-end of PBX1 was shown to result from the translocation. Both genes are known to be targeted also by other neoplasia-specific translocations, PBX1 in acute lymphoblastic leukemia and EWSR1 in several solid tumors, most of which are malignant. Based on the structure of the novel fusion gene detected, its transforming mechanism is thought to be the same as for other fusion genes involving EWSR1 or PBX1.

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Aberrant expression of the LHX4 LIM‐homeobox gene caused by t(1;14)(q25;q32) in chronic myelogenous leukemia in biphenotypic blast crisis

Cited by 16 publications

References 21 publications

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

The (Epi)genetics of human synovial sarcoma

Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1‐PBX1 fusion gene in a myoepithelioma

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