High GATA2 expression is a poor prognostic marker in pediatric acute myeloid leukemia

Abstract

In acute myeloid leukemia (AML), aberrant expression and mutations of transcription factors have been correlated with disease outcome. In the present study, we performed expression and mutation screening of GATA2, which is an essential transcription factor for regulation of myeloid lineage determination, in de novo pediatric AML patients. GATA2 mutations were detected in 5 of 230 patients, representing a frequency of 2.2% overall and 9.8% in cytogenetically normal AML. GATA2 expression analysis demonstrated that in 155 of 237 diagnostic samples (65%), GATA2 expression was higher than in normal BM. In complete remission, normalization of GATA2 expression was observed, whereas GATA2 expression levels stayed high in patients with resistant disease. High GATA2 expression at diagnosis was an independent poor prognostic factor for overall survival (hazard ratio [HR] ‫؍‬ 1.7, P ‫؍‬ .045), event-free survival (HR ‫؍‬ 2.1, P ‫؍‬ .002), and disease-free survival (HR ‫؍‬ 2.3, P ‫؍‬ .004). The prognostic impact of GATA2 was particularly evident in specific AML subgroups. In patients with French-American-British M5 morphology, inv(16), or high WT1 expression, significant differences in survival were observed between patients with high versus normal GATA2 expression. We conclude that high GATA2 expression is a novel poor prognostic marker in pediatric AML, which may contribute to better risk-group stratification and risk-adapted therapy in the future.

Low-level GATA2 overexpression promotes myeloid progenitor self-renewal and blocks lymphoid differentiation in mice

“…Consistent with this possibility, GATA2 is overexpressed in the BM of both pediatric and adult acute myeloid leukemia patients, and aberrant GATA2 expression is also observable in leukemic blasts [7][8][9][10]. Patients in remission display GATA2 levels that return to normal, whereas patients with resistant disease display continued GATA2 overexpression [8].…”

Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia

“…GATA2 is a key regulator of hematopoietic stem cell 32 and megakaryocyte development, 46 and high GATA2 expression has recently been reported as a poor prognostic factor in pediatric AML. 31 HEY2 is largely recognized as a regulator of 47 but was shown to act upstream of Notch to induce hematopoietic stem cell formation in zebrafish embryos. 33 The involvement of both HEY2 and GATA2 in early hematopoiesis, their increased expression in human AML progenitors, 20 and their overexpression specifically in TgERG myeloid but not lymphoid leukemia (supplemental Figure 9) suggest a role for both transcription factors in sustaining the immature nature of ERGinduced myeloid leukemia.…”

“…GATA2 is an important regulator early in hematopoiesis and is perturbed in hematologic malignancies. [30][31][32] Moreover, ERG was shown to be a direct upstream regulator of GATA2 during the second wave of hematopoiesis. 2 Involvement of the bHLH transcription factor Hey2 in hematopoietic stem cell specification in zebrafish has been recently suggested.…”

Haematopoietic and immune defects associated with GATA2 mutation

“…The incidence in unselected cases of MDS or AML is actually quite low, at <5%, and may include cases of GATA2 germ-line mutation that were assumed to be somatic, in the absence of a germ-line DNA control (Yan et al, 2011;Luesink et al, 2012;Papaemmanuil et al, 2013;Shiba et al, 2014). Gain of function mutation L359V has been documented in blast transformation of CML, associated with typically poor outlook (Zhang et al, 2008(Zhang et al, , 2009.…”