A DNA-binding mutant of TAL1 cooperates with LMO2 to cause T cell leukemia in mice.
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).
Department of Cancer Biology, UMass Medical School, Worcester, MA 01605, USA.
K M
KM
Draheim
N
N
Hermance
Y
Y
Yang
E
E
Arous
J
J
Calvo
M A
MA
Kelliher
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015139:Blotting, Southern; D002454:Cell Differentiation / Q000235:genetics; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D060588:LIM Domain Proteins; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008667:Metalloproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000473:pathology*; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D058127:Transcription Factor 3; C513188:Lmo2 protein, mouse; C489366:Tal1 protein, mouse; C489532:Tcf12 protein, mouse