IntroductionIn 2008, the World Health Organization classification of Tumors of the Hematopoietic and Lymphoid Tissues included "AML with mutated CEBPA" as a provisional favorable prognostic entity, and a routine CEBPA mutation screening was recommended for all acute myeloid leukemia (AML) patients with no detectable chromosomal abnormalities. 1,2 However, only patients with mutations in both CEBPA alleles (biCEBPA-mutated AML) have a prognostically favorable outcome. [3][4][5][6][7] The biCEBPA patients typically have a combination of an N-terminal frameshift mutation leading to a 30-kDa dominant-negative CEBPA isoform and a C-terminal in-frame mutation in the bZIP region, disrupting dimerization and DNA-binding activities of CEBPA. In murine bone marrow transplantation models, distinct but collaborative roles of both types of CEBPA mutations have been detected. 8 Furthermore, a combination of an N-and C-terminal disruption of the CEBPA gene synergistically resulted in fast and efficient development of leukemia in mice. [8][9][10] These experiments suggest that a biallelic disruption of CEBPA might be responsible for both the differentiation block and the enhanced proliferation of progenitor cells and thus be sufficient for leukemogenesis. Indeed, biCEBPA mutant AML represents as a very homogeneous AML subgroup with a distinct immunophenotype 11 and a characteristic gene expression profile. 3,6,7,12 Furthermore, biCEBPA mutant AML patients rarely have mutations in genes that are frequently mutated in CN-AML, such as the nucleophosmin (NPM1) gene, internal tandem duplications (ITDs) of the FLT3 gene, partial tandem duplications (PTDs) of the MLL gene (MLL-PTD), [3][4][5] or mutations in the TET2, isocitrate dehydrogenase (IDH)-1 and 2 or DNMT3A genes. [13][14][15] To identify potentially cooperating mutations associated with biCEBPAmutated AML, we performed whole exome sequencing. Thereby, we discovered a high frequency of N-terminal zinc finger (ZF1) mutations of GATA2 in patients with biCEBPA-mutated AML. GATA2 is a zinc finger transcription factor important for hematopoietic stem cell proliferation [16][17][18][19] and normal megakaryocytic development. 20 Somatic mutations affecting the C-terminal zinc finger (ZF2) of GATA2 are associated with the progression of chronic myeloid leukemia (CML), 21 Submitted January 12, 2012; accepted The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From whereas hereditary GATA2 ZF2 mutations predispose to AML and myelodysplastic syndrome. 22 Mutations targeting either of the 2 ZFs were described as a rare event in the M5 subtype of AML. 23 Here, we report a unique association of GATA2 ZF1 mutations and biCEBPA mutations in AML.
Methods
PatientsIn this analysis, we included diagnostic bone marrow or peripheral blood samples from 160 adult AML p...
