Acquisition of additional genetic and/or epigenetic abnormalities other than BCR/ABL fusion gene is believed to cause disease progression in chronic myeloid leukemia (CML) from chronic phase to blast phase. To gain insights into the underlying mechanisms, we screened DNA samples from CML patients during acute transformation for alterations in a number of transcription factor genes crucial to 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. L359V within zinc finger domain (ZF) 2 of GATA-2 was found in 8 cases with myelo-monoblastic features, while an in-frame deletion of six amino acids (D341–346) across the border of ZF1 was detected in 1 patient at blast crisis with eosinophilia. Further studies showed that L359V not only increased transactivation activity, but also enhanced inhibitory effects on the major myelopoietic regulator PU.1. Consistent with the myelo-monoblastic features of CML patients with GATA-2 L359V mutant, transduction of GATA-2 L359V mutant into HL-60 cells or BCR/ABL-harboring mouse model disturbed myelo-monocytic differentiation/proliferation in vitro and in vivo, respectively. These data suggest that GATA-2 mutations may be involved in acute myeloid transformation in some CML patients.

Author notes

Disclosure: No relevant conflicts of interest to declare.