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Background  Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis.    Methods  To understand the molecular bases of aneuploid acute myeloid leukemia (A‐AML), this study examined the genomic profile in 42 A‐AML cases and 35 euploid acute myeloid leukemia (E‐AML) cases.    Results  A‐AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E‐AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg,  SLX4IP ,  RINT1 ,  HINT1 , and  ATR ) and the cell cycle (eg,  MCM2 ,  MCM4 ,  MCM5 ,  MCM7 ,  MCM8 ,  MCM10 ,  UBE2C ,  USP37 ,  CK2 ,  CK3 ,  CK4 ,  BUB1B ,  NUSAP1 , and  E2F ) in A‐AML, which was associated with a 3‐gene signature defined by  PLK1  and  CDC20  upregulation and  RAD50  downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A‐AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E‐AML was associated with  BCOR / BCORL1  mutations and  HOX  gene overexpression.    Conclusions  These findings indicate that aneuploidy‐related and leukemia‐specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery