The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in UBTF in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with co-occurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. Additionally, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.
Registers of children with uncommon conditions have well-established roles in epidemiology, planning and research. By fully involving parents in ways suggested by this study, registers can also empower parents. The study should also provide reassurance to those who hold such registers without explicit consent that the requirement to now obtain consent should not create resentment or jeopardize completeness.
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