Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts.

The ETV6/RUNX1 (E/R) gene fusion is generated by the t(12;21) and found in approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia. In contrast to the overwhelming evidence that E/R is critical for the initiation of leukemia, its relevance for the maintenance of overt disease is less clear. To investigate this issue, we suppressed the endogenous E/R fusion protein with lentivirally transduced short hairpin RNA in the leukemia cell lines REH and AT-2, and found a distinct reduction of proliferation and cell survival.

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling.

Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1 fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias.

TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a.

There is increasing evidence that miRNA and transcription factors interact in an instructive fashion in normal and malignant hematopoiesis. We explored the impact of TEL-AML1 (ETV6-RUNX1), the most common fusion protein in childhood leukemia, on miRNA expression and the leukemic phenotype. Using RNA interference, miRNA expression arrays, and quantitative polymerase chain reaction, we identified miRNA-494 and miRNA-320a to be up-regulated upon TEL-AML1 silencing independently of TEL expression.

ETV6/RUNX1 abrogates mitotic checkpoint function and targets its key player MAD2L1.

Approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia have an ETV6/RUNX1 (E/R) gene fusion that results from a t(12;21). This genetic subgroup of leukemia is associated with near-triploidy, near-tetraploidy, and trisomy 21 as rather specific types of secondary changes. Here, we show that, unlike various controls, E/R-expressing Ba/F3 clones acquire a tetraploid karyotype on prolonged culture, corroborating the assumption that E/R may attenuate the mitotic checkpoint (MC).

Role of the erythropoietin receptor in ETV6/RUNX1-positive acute lymphoblastic leukemia.

Purpose: We explored the mechanisms leading to the distinct overexpression of EPOR as well as the effects of EPO signaling on ETV6/RUNX1-positive acute lymphoblastic leukemias.

Experimental Design: ETV6/RUNX1-expressing model cell lines and leukemic cells were used for real-time PCR of EPOR expression. Proliferation, viability, and apoptosis were analyzed on cells exposed to EPO, prednisone, or inhibitors of EPOR pathways by [3H]thymidine incorporation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and Annexin V/propidium iodide staining.