Clinical impact of GATA2 mutations in acute myeloid leukemia patients harboring CEBPA mutations: a study of the AML study group

Abstract

Conflict of interest:The authors declare no relevant conflict of interest in relation to the work described.AML with biallelic mutations in the CCAAT/enhancer-binding-protein-alpha gene (CEBPA bi ) 1 has now been included in the 2016 revision of the World Health Organization (WHO) 2 classification of myeloid neoplasms as a definite entity due to its association with distinct 3 biological and clinical features as well as its prognostic significance. 1 Mutations in CEBPA 4 (CEBPA mut ) predominantly occur in acute myeloid leukemia (AML) with normal cytogenetics 5 (CN; ~15%), and approximately 60% of the mutated cases carry biallelic mutations. Several 6 studies concordantly showed that in particular patients with CEBPA bi have a favorable 7 outcome compared to monoallelic mutated or wildtype CEBPA (CEBPA wt ) patients. 2,3 8Recently, mutations in the transcription factor GATA2 were identified as genetic lesions 9 potentially cooperating with CEBPA bi with a co-incidence of 18-41%. 4,5 Both, CEBPA and 10 GATA2 are involved in the control of proliferation and differentiation of myeloid progenitors, 11 and germline mutations in both genes have been found predisposing affected individuals for 12 the development of AML. 3,6 GATA2 knockout mice suffer from severe anemia and die around 13 3 day ten of embryonic development. 7 Data from functional studies showed that there is an 14 important interplay between the two genes, e.g. through direct protein-protein-interaction. 8 In 15addition, the C/EBPα dependent activation of target genes is enhanced through 16 coexpression of GATA2 wt . Finally, preliminary data suggest that GATA2 mut allow further 17 refinement of CEBPA mut AML patients with regard to their clinical outcome. 5 18In our study we evaluated the frequency and the clinical impact of GATA2 mut within a large 19 cohort of CEBPA mut AML patients. In total 202 AML patients (age 18 to 78 years) with 20 CEBPA single (CEBPA sm , n=89) or CEBPA bi (n=113) mutations were analyzed for the 21 presence of concurrent GATA2 mut . All patients were enrolled in one of 6 AMLSG treatment 22 trials applying intensive therapy [AMLHD93 n=15; 9 AMLHD98A (NCT00146120) n=53; 23 AMLHD98B n=13; 10 AMLSG 07-04 (NCT00151242) n=74; AMLSG 06-04 (NCT00151255) 24 n=25 and AMLSG 12-09 (NCT01180322) n=22]. The clinical studies were approved by the 25 local ethics review committees and all patients gave informed consent for treatment, 26 molecular analysis and cryopreservation of leukemia samples according to the Declaration of 27Helsinki. In the AMLHD 98B-and AMLSG 06-04 trials patients over the age of 60 were 28 enrolled. The AMLSG 12-09 trial had no upper age limit. In the remaining trials patients 18 to 29 60 years of age were eligible. GATA2 mut screening was performed using a DNA-based PCR-30 assay covering exons 2 to 6 followed by Sanger sequencing. 4 31Among the 202 CEBPA mut AML patients, we identified 42 GATA2 mut in 40 of the 202 patients 32 (20%). Within the subgroup of CEBPA bi mutated patients 38 GATA2 mut were identified in 36 33 o...

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

“…In addition, GATA2 gene mutations are also found in de novo AML [175,176], being mainly concentrated within the exon 3 which encodes for the zinc finger domain 1, with a frequency near to 4%, which rises to 12% in the FAB M4 subtype [177]. Interestingly, GATA2 mutations are often associated with CEBPA biallelic mutations and, with lower incidence, to NPM1 and FLT3 mutations [176,178]. Furthermore, patients harboring both CEBPA biallelic and GATA2 mutations show a more favorable prognosis and better OS than those with CEBPA biallelic mutations alone [175].…”

The GATA factor revolution in hematology

“…(A) Left, GATA-2 N-finger mutations in human AML patients with biallelic CEBPA mutations. [160][161][162][163]174,175 V296 corresponds to GATA-1 V205, which enhances GATA-1 and FOG-1 binding. Right, C-finger mutations identified in AML-associated diseases.…”

“…159 In AML patients with biallelic CEBPA mutations, GATA2 mutations are present with frequencies of ;30% of patients, with most mutations being N-finger missense. [160][161][162] N-finger mutations were described in 22% of patients with acute erythroid leukemia. 163 Although N-finger mutations are known to disrupt GATA-1 function in humans 164 and experimental models, 165,166 how N-fingers mutations impact GATA-2 function is unknown ( Figure 4A).…”

GATA2 mutations in myeloid malignancies: Two zinc fingers in many pies

“…Therefore, they stated that the mutational GATA2 status does not allow to further refine risk stratification of this disease category. 23 In a study by Gröschel et al, GATA2 was the most commonly mutated transcription factor in inv(3)/t(3;3) myeloid malignancies with 15% prevalence and all occurred in ZF1 or ZF2. Furthermore, GATA2 mutations were negatively correlated with RUNX1 mutations, but enriched in samples with SF3B1 mutations.…”

“…In their study, mutations in GATA2 did not impact clinical outcome, neither in the overall AML patient cohort nor in distinct patient subgroups. Therefore, they stated that the mutational GATA2 status does not allow to further refine risk stratification of this disease category …”