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Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the  B-cell translocation gene 1  ( BTG1 ), in a large cohort of pediatric ALL cases.  BTG1  was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the  BTG1  gene, resulting in the expression of truncated  BTG1  read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the  BTG1  gene body in BCP-ALL cells, but not T-ALL cells.  BTG1  deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the  ETV6-RUNX1  and  BCR-ABL1  positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional  BTG1  deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that  BTG1  deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL.

The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution