Open AccessSix1 regulates leukemia stem cell maintenance in acute myeloid leukemia
Author(s) -
Chu Yajing,
Chen Yangpeng,
Li Mengke,
Shi Deyang,
Wang Bichen,
Lian Yu,
Cheng Xuelian,
Wang Xiaomin,
Xu Mingjiang,
Cheng Tao,
Shi Jun,
Yuan Weiping
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14033
Subject(s) - myeloid leukemia , leukemia , cancer research , gene knockdown , transcription factor , haematopoiesis , biology , progenitor cell , stem cell , immunophenotyping , myeloid , immunology , apoptosis , gene , flow cytometry , microbiology and biotechnology , genetics
Molecular genetic changes in acute myeloid leukemia (AML) play crucial roles in leukemogenesis, including recurrent chromosome translocations, epigenetic/spliceosome mutations and transcription factor aberrations. Six1, a transcription factor of the Sine oculis homeobox (Six) family, has been shown to transform normal hematopoietic progenitors into leukemia in cooperation with Eya. However, the specific role and the underlying mechanism of Six1 in leukemia maintenance remain unexplored. Here, we showed increased expression of SIX1 in AML patients and murine leukemia stem cells (c‐Kit + cells, LSCs). Importantly, we also observed that a higher level of Six1 in human patients predicts a worse prognosis. Notably, knockdown of Six1 significantly prolonged the survival of MLL‐AF9‐induced AML mice with reduced peripheral infiltration and tumor burden. AML cells from Six1 ‐knockdown (KD) mice displayed a significantly decreased number and function of LSC, as assessed by the immunophenotype, colony‐forming ability and limiting dilution assay. Further analysis revealed the augmented apoptosis of LSC and decreased expression of glycolytic genes in Six1 KD mice. Overall, our data showed that Six1 is essential for the progression of MLL‐AF9‐induced AML via maintaining the pool of LSC.