APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL

Abstract

Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well.

Apolipoprotein B mRNA editing enzyme catalytic polypeptide‐like family genes activation and regulation during tumorigenesis

“…APOBEC‐mediated mutations not only occur in coding genes, but also take place in non‐coding regions resulting in oncogenic driver genes expression. For example, APOBEC‐like cytidine deaminase mutation at 4 kb upstream of LIM Domain Only 1 (LMO1) oncogene in T‐cell acute lymphoblastic leukemia generates a new MYB transcription factor binding site, which forms an aberrant transcriptional enhancer complex, leading to overexpression of the LMO1 gene …”

“…37 APOBEC-mediated mutations not only occur in coding genes, but also take place in non-coding regions resulting in oncogenic driver genes expression. 38 Increasing evidence show that a germline APOBEC3B deletion resulting in an APOBEC3A_APOBEC3B fusion variant increases the risk of breast cancer 39,40 and increases tumor mutational burden. 41 Recent studies support that APOBEC3 activities are associated with tumorigenesis as a result of increased mutagenesis.…”

Altered TERT promoter and other genomic regulatory elements: occurrence and impact

“…One of the earliest reports of noncoding mutations affecting an enhancer element pertains to the acquired somatic insertions upstream of TAL1 oncogene in T‐cell acute lymphoblastic leukemia (T‐ALL) . Similarly, a C > T somatic noncoding mutation 4 kb upstream of the transcriptional site of the LMO1 oncogene was also reported in T‐ALL . Other noncoding mutations reported include those in the NFKBIE promoter in desmoplastic melanoma and at the transcription start site of RPS27 in melanoma .…”

“…77 Similarly, a C > T somatic noncoding mutation 4 kb upstream of the transcriptional site of the LMO1 oncogene was also reported in T-ALL. 78 Other noncoding mutations reported include those in the NFKBIE promoter in desmoplastic melanoma and at the transcription start site of RPS27 in melanoma. 79,80 Mutations within the 3' untranslated regions of NOTCH1 and CD274 have been reported in chronic lymphocytic leukemia and multiple cancers, respectively.…”

“…77 Similarly, the C > T somatic mutation in noncoding sequences 4 kb upstream of transcriptional start site of the LMO1 in T-ALL, generates a new binding site for the MYB transcription factor leading to the formation of an aberrant transcriptional complex that drives up the expression the LMO1 oncogene. 78 The mutations detected in 3' UTR of NOTCH1 result in novel splicing events in chronic lymphocytic leukemia. 81 The small intergenic region of chromosome 9p13 with recurrent mutations in chronic lymphocytic leukemia was shown to be enriched for lymphocyte-specific transcription factor binding sites and histone marks related to enhancer elements in a lymphoblastoid B-cell line.…”