T(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)

Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
Blood (Impact Factor: 10.45). 02/2008; 111(1):387-91. DOI: 10.1182/blood-2007-07-092015
Source: PubMed


Translocations involving the immunoglobulin heavy chain locus (IGH@) at chromosome band 14q32 are common in mature B-cell neoplasms, but are rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here, we report the translocation, t(6;14)(p22;q32), involving IGH@ as a novel recurrent translocation in 13 BCP-ALL patients. Fluorescence in situ hybridization and long-distance inverse polymerase chain reaction (PCR) identified ID4 as the partner gene. Breakpoints were scattered over a 19kb region centromeric of ID4. Quantitative real-time PCR showed up-regulation of ID4 mRNA. All patients had deletions of CDKN2A and PAX5 located on the short arm of chromosome 9, frequently as a result of an isochromosome, i(9)(q10) (9/13, 69%). This study defines a new subgroup of BCP-ALL characterized by ID4 over-expression and CDKN2A and PAX5 deletions. Preliminary survival data suggest that this subgroup may be associated with a good response to therapy.

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    • "The most common IGH@ partners include CRLF2 (cytokine receptor-like factor 2) at the pseudoautosomal region 1 (PAR1) of Xp22.3/Yp11.3 (resulting in overexpression of CRLF2) [47], ID4 (inhibitor of DNA binding 4) at 6p22 [48], and members of the CEBP (CCAAT/enhancer binding protein) family [49,50]. Translocations between IGH@ and EPOR (erythropoietin receptor) at 19p13 have also been reported [51-53], with other remaining translocations appearing sporadic [46]. "
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    ABSTRACT: In the pediatric population, B-acute lymphoblastic leukemia (B-ALL) is the most prevalent childhood hematological malignancy, as well as the leading cause of childhood cancer-related mortality. Advances in cytogenetics utilizing array-based technologies and next-generation sequencing (NGS) techniques have revealed exciting insights into the genetic basis of this disease, with the hopes of developing individualized treatment plans for affected children. In this comprehensive review, we discuss our current understanding of childhood (pediatric) B-ALL and highlight the most recent genetic advances and their therapeutic implications.
    Full-text · Article · Jun 2014
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    • "Majority of studies have demonstrated tumor suppressor activity of Id4 which is largely based on the evidence that it is epigenetically silencing in cancers such as leukemia [8], breast [9,10], colorectal [11] mouse and human CLL (chronic lymphocytic leukemia [12]) and gastric cancer [13]. High Id4 expression is observed in bladder [14] and rat mammary gland carcinomas, [15], whereas chromosomal translocation of Id4 (t(6;14)(p22;q32)) was found in B-cell acute lymphoblastic leukemia [16] and B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [17], suggesting that it may also have tumor promoter activity. "
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    ABSTRACT: The mechanisms that can restore biological activity of mutant p53 are an area of high interest given that mutant p53 expression is observed in one third of prostate cancer. Here we demonstrate that Id4, an HLH transcriptional regulator and a tumor suppressor, can restore the mutant p53 transcriptional activity in prostate cancer cells. Id4 was over-expressed in prostate cancer cell line DU145 harboring mutant p53 (P223L and V274F) and silenced in LNCaP cells with wild type p53. The cells were used to quantitate apoptosis, p53 localization, p53 DNA binding and transcriptional activity. Immuno-precipitation/-blot studies were performed to demonstrate interactions between Id4, p53 and CBP/p300 and acetylation of specific lysine residues within p53. Ectopic expression of Id4 in DU145 cells resulted in increased apoptosis and expression of BAX, PUMA and p21, the transcriptional targets of p53. Mutant p53 gained DNA binding and transcriptional activity in the presence of Id4 in DU145 cells. Conversely, loss of Id4 in LNCaP cells abrogated wild type p53 DNA binding and transactivation potential. Gain of Id4 resulted in increased acetylation of mutant p53 whereas loss of Id4 lead to decreased acetylation in DU145 and LNCaP cells respectively. Id4 dependent acetylation of p53 was in part due to a physical interaction between Id4, p53 and acetyl-transferase CBP/p300. Taken together, our results suggest that Id4 regulates the activity of wild type and mutant p53. Id4 promoted the assembly of a macromolecular complex involving CBP/P300 that resulted in acetylation of p53 at K373, a critical post-translational modification required for its biological activity.
    Full-text · Article · Dec 2013 · Molecular Cancer
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    • "Epigenetic silencing of Id4 in leukemia [19], breast [20,21], colorectal [22] mouse and human CLL (chronic lymphocytic leukemia [23]) and gastric cancer [24] tend to support its anti-tumor activity. Whereas high Id4 expression is reported in B-cell acute lymphoblastic leukemia [25] and B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [26] due to the t(6;14)(p22;q32) chromosomal translocation, and in bladder [27] and rat mammary gland carcinomas [28] suggests that it may also have pro-tumor activity. "
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    ABSTRACT: Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer. Id4 is expressed in the normal prostate where its expression is also regulated by androgens. In this study we investigated the effect of loss of Id4 (Id4-/-) on adult prostate morphology. Histological analysis was performed on prostates from 6-8 weeks old Id4-/-, Id4+/- and Id4+/+ mice. Expression of Id1, Sox9, Myc, androgen receptor, Akt, p-Akt, Pten and Nkx3.1 was investigated by immunohistochemistry. Androgen receptor binding on NKX3.1 promoter was studied by chromatin immuno-precipitation. Id4 was either over-expressed or silenced in prostate cancer cell lines DU145 and LNCaP respectively followed by analysis of PTEN, NKX3.1 and Sox9 expression. Id4-/- mice had smaller prostates with fewer tubules, smaller tubule diameters and subtle mPIN like lesions. Levels of androgen receptor were similar between wild type and Id4-/- prostate. Decreased NKX3.1 expression was in part due to decreased androgen receptor binding on NKX3.1 promoter in Id4-/- mice. The increase in the expression of Myc, Sox9, Id1, Ki67 and decrease in the expression of PTEN, Akt and phospho-AKT was associated with subtle mPIN like lesions in Id4-/- prostates. Finally, prostate cancer cell line models in which Id4 was either silenced or over-expressed confirmed that Id4 regulates NKX3.1, Sox9 and PTEN. Our results suggest that loss of Id4 attenuates normal prostate development and promotes hyperplasia/dysplasia with subtle mPIN like lesions characterized by gain of Myc and Id1 and loss of Nkx3.1 and Pten expression. One of the mechanisms by which Id4 may regulate normal prostate development is through regulating androgen receptor binding to respective response elements such as those on NKX3.1 promoter. In spite of these complex alterations, large neoplastic lesions in Id4-/- prostates were not observed suggesting the possibility of mechanisms/pathways such as loss of Akt that could restrain the formation of significant pre-cancerous lesions.
    Full-text · Article · Jun 2013 · Molecular Cancer
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