E Protein Transcription Factors as Suppressors of T Lymphocyte Acute Lymphoblastic Leukemia

Abstract

T Lymphocyte Acute Lymphoblastic Leukemia (ALL) is an aggressive disease arising from transformation of T lymphocytes during their development. The mutation spectrum of T-ALL has revealed critical regulators of the growth and differentiation of normal and leukemic T lymphocytes. Approximately, 60% of T-ALLs show aberrant expression of the hematopoietic stem cell-associated helix-loop-helix transcription factors TAL1 and LYL1. TAL1 and LYL1 function in multiprotein complexes that regulate gene expression in T-ALL but they also antagonize the function of the E protein homodimers that are critical regulators of T cell development. Mice lacking E2A, or ectopically expressing TAL1, LYL1, or other inhibitors of E protein function in T cell progenitors, also succumb to an aggressive T-ALL-like disease highlighting that E proteins promote T cell development and suppress leukemogenesis. In this review, we discuss the role of E2A in T cell development and how alterations in E protein function underlie leukemogenesis. We focus on the role of TAL1 and LYL1 and the genes that are dysregulated in E2a^-/- T cell progenitors that contribute to human T-ALL. These studies reveal novel mechanisms of transformation and provide insights into potential therapeutic targets for intervention in this disease.

Keywords: E protein; LYL1; Leukemia; T lymphocyte; TAL1; murine.

Figure 1

Schematic representation of T cell development in WT and E2a^-/- mice. T cell development in WT mice is depicted in the top half of the figure. Tal1:E2A (or E protein) dimers are prevalent in HSCs and decline as progenitors differentiate toward the T cell lineage. At the time of thymic commitment E2a:HEB dimers dominate. NOTCH1 and GATA3 start to be expressed upon thymic entry, along with TCF1 (not depicted) under the influence of NOTCH1 ligands in the thymus. LEF1 expression initiates with commitment to the T lymphocyte lineage but remains low throughout T cell development. T cell development in E2a^-/- mice is depicted on the lower half of the figure. Here, Tal1:HEB or E2-2 dimers control early hematopoiesis resulting in a reduced number of thymic seeding progenitors that can only express HEB : HEB or E2-2 dimers after extinction of TAL1 expression. GATA3 expression is high and diverts progenitors toward the ILC/NK fate. Mutations in the Notch1 gene accumulate and LEF1 is expressed at very high levels. Combined, these alterations in NOTCH1, GATA3 and LEF1 contribute to T cell transformation.

Figure 2

The TAL1 genomic locus and mutations leading to ectopic expression in T lymphocytes and T-ALL. The WT TAL1 locus is depicted downstream of the STIL gene. TAL1 transcription is increased in T lymphocytes through genomic translocation into the TCRB/A/D locus, through genomic deletions bringing the STIL enhancer close to TAL1 or through insertions that create a novel MYB binding enhancer upstream of TAL1.