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Tcrδtranslocations that delete theBcl11bhaploinsufficient tumor suppressor gene promote atm-deficient T cell acute lymphoblastic leukemia
| Content Provider | Scilit |
|---|---|
| Author | Ehrlich, Lori A. Yang-Iott, Katherine Bassing, Craig H. |
| Copyright Year | 2014 |
| Description | Journal: Cell Cycle ATM is the master regulator of the cellular response to DNA double strand breaks (DSBs). Deficiency of ATM predisposes humans and mice to αβ T lymphoid cancers with clonal translocations between the T cell receptor (TCR) α/δ locus and a 450 kb region of synteny on human chromosome 14 and mouse chromosome 12. While these translocations target and activate the TCL1 oncogene at 14q32 to cause T cell pro-lymphocytic leukemia (T-PLL), the TCRα/δ;14q32 translocations in ATM-deficient T cell acute lymphoblastic leukemia (T-ALL) have not been characterized and their role in cancer pathogenesis remains unknown. The corresponding lesion in Atm-deficient mouse T-ALLs is a chromosome t(12;14) translocation with Tcrδ genes fused to sequences on chromosome 12; although these translocations do not activate Tcl1, they delete the Bcl11b haploinsufficient tumor suppressor gene. To assess whether Tcrδ translocations that inactivate one copy of Bcl11b promote transformation of Atm-deficient cells, we analyzed Atm(-/-) mice with mono-allelic Bcl11b deletion initiating in thymocytes concomitant with Tcrδ recombination. Inactivation of one Bcl11b copy had no effect on the predisposition of Atm(-/-) mice to clonal T-ALLs. Yet, none of these T-ALLs had a clonal chromosome t(12;14) translocation that deleted Bcl11b indicating that Tcrδ translocations that inactivate a copy of Bcl11b promote transformation of Atm-deficient thymocytes. Our data demonstrate that antigen receptor locus translocations can cause cancer by deleting a tumor suppressor gene. We discuss the implications of these findings for the etiology and therapy of T-ALLs associated with ATM deficiency and TCRα/δ translocations targeting the 14q32 cytogenetic region. |
| Related Links | https://www.tandfonline.com/doi/pdf/10.4161/15384101.2014.949144?needAccess=true https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615123/pdf |
| Ending Page | 3082 |
| Page Count | 7 |
| Starting Page | 3076 |
| ISSN | 15384101 |
| e-ISSN | 15514005 |
| DOI | 10.4161/15384101.2014.949144 |
| Journal | Cell Cycle |
| Issue Number | 19 |
| Volume Number | 13 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2014-10-30 |
| Access Restriction | Open |
| Subject Keyword | Journal: Cell Cycle Research and Experimental Medicine A-t, Ataxia Telangiectasia, Ea, Tcra Transcriptional Enhancer All, Acute Lymphoblastic Leukemia Atm, Ataxia Telangiectasia Mutated Dsb, Dna Double Strand Break Sky, Spectral Karyotyping T-all, T Cell Acute Lymphoblastic Leukemia Tcr, T Cell Receptor Transformation Translocations |
| Content Type | Text |
| Subject | Cell Biology Developmental Biology Medicine Molecular Biology |
