title: 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 (delta341-346) 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.
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.
authors.forename: Su-Jiang
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Ma
authors.forename: Qiu-Hua
authors.initials: QH
authors.lastname: Huang
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Bai-Wei
authors.initials: BW
authors.lastname: Gu
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Gao
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Shi
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Xun
authors.initials: X
authors.lastname: Cai
authors.forename: Rui-Bao
authors.initials: RB
authors.lastname: Ren
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D017931:DNA Primers; D018450:Disease Progression; D050989:GATA2 Transcription Factor / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D050989:GATA2 Transcription Factor