Abstract
Intragenic ERG deletions occur in 3–5% of B-cell precursor acute lymphoblastic leukemia, specifically in B-other subtype lacking the classifying genetic lesions. They represent the only genetic lesion described so far present in the majority of cases clustering into a subgroup of B-other subtype characterized by a unique gene expression profile, probably sharing a common, however, not yet fully described, biological background. We aimed to elucidate whether ERG deletions could drive the specific biology of this ERG-related leukemia subgroup through expression of aberrant or decreased expression of wild type ERG isoforms. We showed that leukemic cells with endogenous ERG deletion express an aberrant transcript translated into two proteins in transfected cell lines and that one of these proteins colocalizes with wild type ERG. However, we did not confirm expression of the proteins in acute lymphoblastic leukemia cases with endogenous ERG deletion. ERG deletions resulted in significantly lower expression of wild type ERG transcripts compared to B-other cases without ERG deletion. However, cases with subclonal ERG deletion, clustering to the same ERG deletion associated subgroup, presented similar levels of wild type ERG as cases without ERG deletion. In conclusion, our data suggest that neither the expression of aberrant proteins from internally deleted allele nor the reduced expression of wild type ERG seem to provide a plausible explanation of the specific biology of ERG -related leukemia subgroup.
Highlights
Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, is a heterogeneous disease driven by a wide range of primary and secondary genetic aberrations
There were 2 bands in cytoplasmic protein fraction of NALM6 cell line detected only by Ab-int but not by the other antibodies. These bands may represent some short ERG isoforms, since we showed that Ab-int detects physiological ERG isoforms but neither ERGaberN nor ERGaberC, these short isoforms probably contain amino acids encoded by region that is not involved in ERGaber transcript and, they are rather expressed from the wild type ERG allele
To better understand the potential biological role of intragenic ERG deletions we aimed to study two possible primary consequences of this aberrations: 1) the expression of aberrant dominant-negative gene products and/or 2) gene dosage dependent reduction of physiological gene products
Summary
Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, is a heterogeneous disease driven by a wide range of primary and secondary genetic aberrations. Intragenic deletions of ERG gene (ERGdel) occur in 3–5% of B-cell precursor (BCP) ALL and are associated with specific clinical features at disease manifestation and during treatment [1, 2]. We showed previously that ERGdel may occur at subclonal level and that it may be lost at disease recurrence [2]. These findings suggest that ERGdel represents a secondary event at least in a proportion of cases. Any other aberration occurring in a majority of cases from the above mentioned GEP-defined ERG-related ALL subtype (potentially defining its common genetic background) has not been identified besides ERGdel so far. Despite possibly representing a secondary event ERGdel may still significantly impact the biological character of this subgroup
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