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A DNA-binding mutant of TAL1 cooperates with LMO2 to cause T cell leukemia in mice

Oncogene volume 30, pages 1252–1260 (2011)Cite this article

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Abstract

The most common translocation in childhood T-cell acute lymphoblastic leukemia (T-ALL) involves the LMO2 locus, resulting in ectopic expression of the LMO2 gene in human thymocytes. The LMO2 gene was also activated in patients with X-linked Severe Combined Immune Deficiency treated with gene therapy because of retroviral insertion in the LMO2 locus. The LMO2 insertions predisposed these children to T-ALL, yet how LMO2 contributes to T cell transformation remains unclear. The LIM (Lin 11, Isl-1, Mec-3) domain containing LMO2 protein regulates erythropoiesis as part of a large transcriptional complex consisting of LMO2, TAL1, E47, GATA1 and LDB1 that recognizes bipartite E-box-GATA1 sites on target genes. Similarly, a TAL1/E47/LMO2/LDB1 complex is observed in human T-ALL and Tal1 and Lmo2 expression in mice results in disease acceleration. To address the mechanism(s) of Tal1/Lmo2 synergy in leukemia, we generated Lmo2 transgenic mice and mated them with mice that express wild-type Tal1 or a DNA-binding mutant of TAL1. Tal1/Lmo2 and MutTAL1/Lmo2 bitransgenic mice exhibit perturbations in thymocyte development due to reduced E47/HEB transcriptional activity and develop leukemia with identical kinetics. These data demonstrate that the DNA-binding activity of Tal1 is not required to cooperate with Lmo2 to cause leukemia in mice and suggest that Lmo2 may cooperate with Tal1 to interfere with E47/HEB function(s).

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Acknowledgements

This work is supported by an NIH/NCI CA096899 Grant to MK. Core resources supported by the Diabetes Endocrinology Research Center Grant DK32520 were also used.

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Authors and Affiliations

  1. Department of Cancer Biology, UMass Medical School, Worcester, MA, USA

    K M Draheim, N Hermance, Y Yang, E Arous & M A Kelliher

  2. Department of Biological Engineering, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    J Calvo

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  1. K M Draheim
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Correspondence to M A Kelliher.

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Draheim, K., Hermance, N., Yang, Y. et al. A DNA-binding mutant of TAL1 cooperates with LMO2 to cause T cell leukemia in mice. Oncogene 30, 1252–1260 (2011). https://doi.org/10.1038/onc.2010.495

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