GATA2 zinc finger 1 mutations are associated with distinct clinico-biological features and outcomes different from GATA2 zinc finger 2 mutations in adult acute myeloid leukemia

Abstract

Mutations of the GATA binding protein 2 (GATA2) gene in myeloid malignancies usually cluster in the zinc finger 1 (ZF1) and the ZF2 domains. Mutations in different locations of GATA2 may have distinct impact on clinico-biological features and outcomes in AML patients, but little is known in this aspect. In this study, we explored GATA2 mutations in 693 de novo non-M3 AML patients and identified 44 GATA2 mutations in 43 (6.2%) patients, including 31 in ZF1, 10 in ZF2, and three outside the two domains. Different from GATA2 ZF2 mutations, ZF1 mutations were closely associated with French-American-British (FAB) M1 subtype, CEBPA double mutations (CEBPAdouble-mut), but inversely correlated with FAB M4 subtype, NPM1 mutations, and FLT3-ITD. ZF1-mutated AML patients had a significantly longer overall survival (OS) than GATA2-wild patients and ZF2-mutated patients in total cohort as well as in those with intermediate-risk cytogenetics and normal karyotype. ZF1 mutations also predicted better disease-free survival and a trend of better OS in CEBPAdouble-mut patients. Sequential analysis showed GATA2 mutations could be acquired at relapse. In conclusion, GATA2 ZF1 mutations are associated with distinct clinico-biological features and predict better prognosis, different from ZF2 mutations, in AML patients.

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

“…Somatic GATA2 mutations show overall reduced transactivation potential with a few exceptions and skew the differentiation of hematologic progenitors towards the granulocytic linage . So far, somatic mutations in GATA2 ZF1 have been shown to co‐occur with mutations in CEBPA and SF3B1 , FAB M1 subtype, AEL and t(3;3) AML and to be mutually exclusive with mutations in NPM1 , RUNX1 , and FLT3 ‐ITD and FAB M4 AML . The L359V mutant was earlier described to be exclusively associated with CML, whereas more recent studies show an association with BCR‐ABL‐negative AML .…”

“…So far, somatic mutations in GATA2 ZF1 have been shown to co‐occur with mutations in CEBPA and SF3B1 , FAB M1 subtype, AEL and t(3;3) AML and to be mutually exclusive with mutations in NPM1 , RUNX1 , and FLT3 ‐ITD and FAB M4 AML . The L359V mutant was earlier described to be exclusively associated with CML, whereas more recent studies show an association with BCR‐ABL‐negative AML . The prognostic value of somatic GATA2 mutations remains controversial.…”

“…Additionally, somatic GATA2 mutations are either lost or acquired as the disease progresses . The fact that somatic GATA2 mutations frequently arise during AML relapse suggests a role of GATA2 in chemotherapy resistance …”

“…Consistent with the previous studies of adult AML, GATA2 mutations localized predominantly in the ZF1 region. In addition, the authors reported two novel AML missense somatic mutations, one of them being the ZF2 mutant L359V, and that some patients acquired GATA2 ZF1 mutations at relapse being R307L, G320D, L321P, and L321H …”

“…Somatic GATA2 mutations mainly cluster in the two ZF domains and are associated with specific leukemia subtypes, like CML progression to blast crisis, or AML with CCAAT/enhancer‐binding protein alpha (CEBPA) mutations . Phenotypic correlations and defined mutational clustering distinguish ZF1 and ZF2 GATA2 mutations, indicating that they may represent fundamentally different leukemogenic mechanisms . In this review, we summarize the current understanding and controversies of GATA2 ZF mutations in the context of their clinical correlations and functional consequences.…”