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

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).

Characterization of a pediatric T-cell acute lymphoblastic leukemia patient with simultaneous LYL1 and LMO2 rearrangements

“…[18][19][20] Lmo1/Lmo2 and Tal1 have also been shown to synergize to T-cell leukemogenesis in mice studies. 18,[21][22][23] To conclude, we suggest that LYL1 rearranged cases are not part of the immature, ETP-ALL subgroup, but belong to the TALLMO subgroup. LYL1 translocations fulfill a TAL1-like role that can synergize with LMO2 aberrations in T-cell oncogenesis.…”

Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL

“…17 To generate the Tal/Lmo2/TNR cohort, Tal/Lmo2 mice were mated with TNR/ϩ mice (STOCK Tg(Cp-EGFP)25Gaia/J no. 005854; The Jackson Laboratory).…”

Rat Stem-Cell Leukemia Gene Expression Increased during Testis Maturation

“…Rat Gapdh amplifications are indicated at the bottom. B, Tal-1 RT-PCR transcript analysis of human fetal liver: Flv (63 spontaneously aborted male and female Caucasian fetus, ages 22-40 weeks), adult liver: Lv (51-year-old male Caucasian), bone marrow: Bm (56 Asian males and females, ages 22-95) and testis: Te (five Asians, ages [21][22][23][24][25][26][27][28][29]. Human GAPDH amplifications are indicated at the bottom.…”

“…Human total RNA was purchased (Takara Bio, Shiga, Japan). Fetal liver RNA was prepared from 63 spontaneously aborted male and female Caucasian fetuses (ages 22-40 weeks), liver RNA was from a 51-year-old male Caucasian, bone marrow RNA was from 56 Asian males and females (ages 22-95), and testis RNA was from five Asians (ages [21][22][23][24][25][26][27][28][29]. cDNA was synthesized from 1 mg of RNA using a firststrand cDNA synthesis kit including Super Script III Reverse Transcriptase (Life Technologies).…”

“…A combination of TAL-1 and LIM domain protein LMO2 has been found to lead to the development of T-ALL. 28) Human Tal-1 expression is largely limited to the fetal liver and to adult bone marrow, brain, and cartilage.…”