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Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery
Author(s) -
Simonetti Giorgia,
Padella Antonella,
do Valle Italo Farìa,
Fontana Maria Chiara,
Fonzi Eugenio,
Bruno Samantha,
Baldazzi Carmen,
Guadagnuolo Viviana,
Manfrini Marco,
Ferrari Anna,
Paolini Stefania,
Papayannidis Cristina,
Marconi Giovanni,
Franchini Eugenia,
Zuffa Elisa,
Laginestra Maria Antonella,
Zanotti Federica,
Astolfi Annalisa,
Iacobucci Ilaria,
Bernardi Simona,
Sazzini Marco,
Ficarra Elisa,
Hernandez Jesus Maria,
Vandenberghe Peter,
Cools Jan,
Bullinger Lars,
Ottaviani Emanuela,
Testoni Nicoletta,
Cavo Michele,
Haferlach Torsten,
Castellani Gastone,
Remondini Daniel,
Martinelli Giovanni
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.31837
Subject(s) - myeloid leukemia , cancer research , aneuploidy , biology , myeloid , rad50 , leukemia , downregulation and upregulation , cell cycle , protein degradation , medicine , cancer , genetics , gene , chromosome , microbiology and biotechnology , dna binding protein , transcription factor
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.