Tal1 and a DNA Binding Mutant (Tal1R188G;R189G) Cooperate with LMO2 To Induce Leukemia in Mice.

LMO2 is a member of the “LIM only” protein family and required for primitive erythropoiesis and adult vasculogenesis and angiogenesis. In erythroid cells, LMO2 interacts with TAL1 and E47 and LDB1 and GATA-1, thereby forming a transcriptional complex whose target genes include EKLF, CKIT, and p4.2 (protein 4.2). LMO2 was first implicated in leukemogenesis when it was identified in chromosomal translocations t(11;14)(p13;q11) and t(7;11)(q35;p13) found in T cell acute lymphoblastic leukemia (T-ALL) patients. Ectopic expression of LMO2 in mice recapitulates the human disease, albeit at low penetrance and following a long latency. LMO2 has been shown to synergize with TAL1, yet the mechanism of oncogene cooperativity is unknown. Two models have been proposed: the first suggests that LMO2 and TAL1 synergize by forming an active transcriptional complex that induces expression of target genes such as retinaldehyde dehydrogenase 2 (RALDH2) and TALLA1 (a surface marker of T-ALL). The second model proposes that LMO2 and TAL1 sequester the E47/HEB heterodimer, resulting in inhibition of E47/HEB-mediated transcription. To distinguish between these models, we mated our Tal1 transgenic mice and our DNA binding mutant of Tal1(R188G:R189G) with Lmo2 transgenic mice. As expected, transgenic expression of Lmo2 induced disease in 23% of mice after 302 days. Similar to published studies, Tal1 and Lmo2 expression dramatically inhibited thymocyte development and induced T cell leukemia in 100% of the mice with a mean latency of 108 days. To test whether the DNA binding properties of tal1 were required to cooperate with LMO2, we mated mice expressing a DNA binding mutant of Tal1(R188G;R189G) with Lmo2 transgenic mice and found that tumors were induced with similar kinetics; 100% of mice developed disease with an average latency of 107 days. These data suggest LMO2 does not require the DNA-binding properties of Tal1 to induce leukemia in mice and support the model that LMO2 contributes to leukemia through E47/HEB sequestration and inhibition.