Novel in-frame deletion of GATA1 observed in pediatric acute megakaryoblastic leukemia without down syndrome

Abstract

    Children with Down syndrome (DS) have an increased incidence of acute megakaryoblastic leukemia (DS-AMKL). Almost all DS-AMKL patients harbor somatic mutations in GATA1. These mutations lead to exclusive expression of the protein lacking the N-terminal domain (GATA1s). Few AMKL patients without DS (non-DS-AMKL) harbor the mutations. Recently, we found a novel GATA1 mutation (c.721_732del) that causes an in-frame deletion of amino acid residues 241-244 in one of 19 non-DS-AMKL cases. The patient who showed leukocytosis from birth was diagnosed with AMKL at one month of age and had a blast cell karyotype of 46,XY. During the validation of the mutation, we identified another large deletion (c.221-33_553del) that results in the splicing of exon 3. Both mutations were located on the same allele. The mutant protein (referred to as #135) revealed decreased transactivation activity (about 60%) compared to full-length GATA1. From cell proliferation assays using DS-AMKL cell line KPAM1, cell proliferation was markedly reduced by transduction with a retrovirus expressing full-length GATA1. In contrast, expression of GATA1s or #135 moderately restricted proliferation. These results indicate that the #135 mutant is involved in the pathogenesis of non-DS-AMKL.