Characterizing the Global Transcriptional Effects of TEL-AML1-Fusion in Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer affecting thousands of children worldwide each year. Most patients are cured but only after long chemotherapy treatment and still 15 % of them relapse. Therefore, better understanding of the molecular biology behind the disease is fundamental. TEL-AML1 fusion - comprised of two transcription factors important in hematopoiesis regulation - is the most frequent genetic variation found in 25 % of pediatric ALL-patients. The translocation occurs during pregnancy and is suggested to serve as a “first hit” enabling secondary changes that lead to cancer formation. Despite its frequency, genetic targets of this aberrant transcription factor are unclear, and its function in leukemia initiation and progression remains elusive.

Here we aim at solving the genome-wide effects of TEL-AML1 on transcription using pre-B-leukemic cell models. After a time-series induction of wild-type or DNA-binding compromised mutated TEL-AML1, or a constitutive expression of shRNA silencing the fusion, the cells were studied using global nuclear run-on sequencing (GRO-seq). GRO-seq technology can map RNA polymerase II location and identify actively transcribed coding and non-coding genes and their directionality. Thus, GRO-seq provides a snapshot of global active transcription and was used here to identify bona fide targets of the TEL-AML1-fusion protein.

In addition to transcriptional changes in known genes, we identified a notable number of novel transcripts including antisense-, lincRNA-, and microRNAs. We also characterized genomic locations where the fusion functions as a direct regulator by taking advantage of non-coding RNA transcripts known as enhancer RNAs. Furthermore, we performed transcription factor motif enrichment analysis on these active regulatory eRNA regions. The results uncover early transcriptional changes induced by TEL-AML1-fusion and may reveal critical steps in leukemia initiation and development. The findings also highlight the importance of non-coding RNAs in the pathogenesis of pediatric leukemia.