Tcrδ translocations that delete the Bcl11b haploinsufficient tumor suppressor gene promote atm-deficient T cell acute lymphoblastic leukemia

10Citations
Citations of this article
13Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

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.

References Powered by Scopus

The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more

1292Citations
N/AReaders
Get full text

A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival

1054Citations
N/AReaders
Get full text

Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma

759Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Pediatric T-cell acute lymphoblastic leukemia

96Citations
N/AReaders
Get full text

The genetics and mechanisms of T-cell acute lymphoblastic leukemia

32Citations
N/AReaders
Get full text

Regulation of Tcrb Gene Assembly by Genetic, Epigenetic, and Topological Mechanisms

29Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Ehrlich, L. A., Yang-Iott, K., & Bassing, C. H. (2014). Tcrδ translocations that delete the Bcl11b haploinsufficient tumor suppressor gene promote atm-deficient T cell acute lymphoblastic leukemia. Cell Cycle, 13(19), 3076–3082. https://doi.org/10.4161/15384101.2014.949144

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 6

75%

Professor / Associate Prof. 1

13%

Researcher 1

13%

Readers' Discipline

Tooltip

Agricultural and Biological Sciences 4

33%

Medicine and Dentistry 4

33%

Biochemistry, Genetics and Molecular Bi... 3

25%

Chemistry 1

8%

Save time finding and organizing research with Mendeley

Sign up for free