Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia

Abstract

Acquisition of additional genetic and/or epigenetic abnormalities other than the BCR/ABL fusion gene is believed to cause disease progression in chronic myeloid leukemia (CML) from chronic phase to blast crisis (BC). To gain insights into the underlying mechanisms of progression to BC, we screened DNA samples from CML patients during blast transformation for mutations in a number of transcription factor genes that are critical for myeloid-lymphoid development. In 85 cases of CML blast transformation, we identified two new mutations in the coding region of GATA-2, a negative regulator of hematopoietic stem/progenitor cell differentiation. A L359V substitution within zinc finger domain (ZF) 2 of GATA-2 was found in eight cases with myelomonoblastic features, whereas an in-frame deletion of 6 aa (⌬341-346) spanning the C-terminal border of ZF1 was detected in one patient at myeloid BC with eosinophilia. Further studies indicated that L359V not only increased transactivation activity of GATA-2 but also enhanced its inhibitory effects on the activity of PU.1, a major regulator of myelopoiesis. Consistent with the myelomonoblastic features of CML transformation with the GATA-2 L359V mutant, transduction of the GATA-2 L359V mutant into HL-60 cells or BCR/ABL-harboring murine cells disturbed myelomonocytic differentiation/proliferation in vitro and in vivo, respectively. These data strongly suggest that GATA-2 mutations may play a role in acute myeloid transformation in a subset of CML patients.blast crisis ͉ chronic phase ͉ genetic alteration ͉ transcriptional regulation

Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

“…The mutation in GATA2, P125T, is located in the transactivation domain, and it is interesting to speculate whether this mutation may promote activation of GATA2-mediated transcription. Indeed, GATA2 has been identified as an essential protein in KRAS-driven lung cancers, and GOF mutations in GATA2 were identified in 7 of 85 patients with chronic myelogenous leukemia in recent studies (35,36). In addition, we identified a small GTPase RasL10b, as a potential mutationally activated enzyme in the H2122 cell line.…”

Haematopoietic and immune defects associated with GATA2 mutation

“…However, it is also possible that these mutants have residual function or can even act in a dominant negative fashion, as reported for T354M (Hahn et al, 2011). Gain of function is reported for the L359V variant found in blast transformation of chronic myeloid leukaemia (CML) (Zhang et al, 2008). Of all the known regulatory regions of GATA2, only the intron 5 enhancer has been reported to contain germ-line mutations (Johnson et al, 2012;Hsu et al, 2013).…”

“…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. In contrast, a high level of mutation (approximately 40%) is observed with bi-allelic mutation of CEBPA, conferring a better prognosis than CEBPA mutation with wild-type GATA2 (Greif et al, 2012;Fasan et al, 2013;Green et al, 2013;Grossmann et al, 2013;Shiba et al, 2014).…”

Heterogeneity of GATA2-related myeloid neoplasms

“…In this process GATA2 expression is regulated by NOTCH1 and BMP4, interacting with other hematopoietic players, involving FLI1, SCL/TAL1 and deficiency or haploinsufficiency has been widely accepted to describe GATA2-related disorders. On the other hand, somatic GATA2 mutations in adult AML can occur in both ZF regions with preference for ZF1 [16,17] and can exhibit both loss-or gain-of-function effects [16,18,19]. Generally, only one GATA2 allele is affected in carriers and (unlike for DDX41 or RUNX1) secondary somatic GATA2 mutations are not detected.…”