Gata2-L359V impairs primitive and definitive hematopoiesis and blocks cell differentiation in murine chronic myelogenous leukemia model

作者：Fu, Ya-Kai; Tan, Yun^*; Wu, Bo; Dai, Yu-Ting; Xu, Xiao-Guang; Pan, Meng-Meng; Chen, Zhi-Wei; Qiao, Niu; Wu, Jing; Jiang, Lu; Lu, Jing; Chen, Bing; Rein, Avigail; Izraeli, Shai; Sun, Xiao-Jian; Huang, Jin-Yan; Huang, Qiu-Hua^*; Chen, Zhu; Chen, Sai-Juan^*

来源：Cell Death & Disease, 2021, 12(6): 568.

DOI：10.1038/s41419-021-03826-1

• STEM-CELLS
• TRANSCRIPTION FACTORS
• LINEAGE COMMITMENT
• GATA2 MUTATIONS
• GENE-EXPRESSION
• CIS-ELEMENT
• BCR-ABL
• ERYTHROPOIETIN
• TRANSFORMATION
• MECHANISMS

GATA2, a key transcription factor in hematopoiesis, is frequently mutated in hematopoietic malignancies. How the GATA2 mutants contribute to hematopoiesis and malignant transformation remains largely unexplored. Here, we report that Gata2-L359V mutation impeded hematopoietic differentiation in murine embryonic and adult hematopoiesis and blocked murine chronic myeloid leukemia (CML) cell differentiation. We established a Gata2-L359V knockin mouse model in which the homozygous Gata2-L359V mutation caused major defects in primitive erythropoiesis with an accumulation of erythroid precursors and severe anemia, leading to embryonic lethality around E11.5. During adult life, the Gata2-L359V heterozygous mice exhibited a notable decrease in bone marrow (BM) recovery under stress induction with cytotoxic drug 5-fluorouracil. Using RNA sequencing, it was revealed that homozygous Gata2-L359V suppressed genes related to embryonic hematopoiesis in yolk sac, while heterozygous Gata2-L359V dysregulated genes related to cell cycle and proliferation in BM Lin(-)Sca1(+)c-kit(+) cells. Furthermore, through chromatin immunoprecipitation sequencing and transactivation experiments, we found that this mutation enhanced the DNA-binding capacity and transcriptional activities of Gata2, which was likely associated with the altered expression of some essential genes during embryonic and adult hematopoiesis. In mice model harboring BCR/ABL, single-cell RNA-sequencing demonstrated that Gata2-L359V induced additional gene expression profile abnormalities and partially affected cell differentiation at the early stage of myelomonocytic lineage, evidenced by the increase of granulocyte-monocyte progenitors and monocytosis. Taken together, our study unveiled that Gata2-L359V mutation induces defective hematopoietic development and blocks the differentiation of CML cells.

• 单位
  中国科学院; 上海交通大学; y