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ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.

ABSTRACT: The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion.

SUBMITTER: Hartmann L 

PROVIDER: S-EPMC4895769 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.

Hartmann Luise L   Dutta Sayantanee S   Opatz Sabrina S   Vosberg Sebastian S   Reiter Katrin K   Leubolt Georg G   Metzeler Klaus H KH   Herold Tobias T   Bamopoulos Stefanos A SA   Bräundl Kathrin K   Zellmeier Evelyn E   Ksienzyk Bianka B   Konstandin Nikola P NP   Schneider Stephanie S   Hopfner Karl-Peter KP   Graf Alexander A   Krebs Stefan S   Blum Helmut H   Middeke Jan Moritz JM   Stölzel Friedrich F   Thiede Christian C   Wolf Stephan S   Bohlander Stefan K SK   Preiss Caroline C   Chen-Wichmann Linping L   Wichmann Christian C   Sauerland Maria Cristina MC   Büchner Thomas T   Berdel Wolfgang E WE   Wörmann Bernhard J BJ   Braess Jan J   Hiddemann Wolfgang W   Spiekermann Karsten K   Greif Philipp A PA  

Nature communications 20160602

The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger  ...[more]

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