Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Yajing Chu, Yangpeng Chen, Mengke Li, Deyang Shi, Bichen Wang, Yu Lian, Xuelian Cheng, Xiaomin Wang, Mingjiang Xu, Tao Cheng, Jun Shi, Weiping Yuan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2200-2210
Number of pages11
JournalCancer Science
Volume110
Issue number7
DOIs
StatePublished - Jul 1 2019
Externally publishedYes

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Acute Myeloid Leukemia
Leukemia
Stem Cells
Maintenance
Transcription Factors
Spliceosomes
Aptitude
Homeobox Genes
Myeloid Cells
Tumor Burden
Epigenomics
Molecular Biology
Chromosomes
Apoptosis
Gene Expression
Mutation
Survival

Keywords

  • acute myeloid leukemia
  • glycolysis
  • leukemia stem cell
  • MLL-rearranged leukemia
  • Six1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chu, Y., Chen, Y., Li, M., Shi, D., Wang, B., Lian, Y., ... Yuan, W. (2019). Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia. Cancer Science, 110(7), 2200-2210. https://doi.org/10.1111/cas.14033

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia. / Chu, Yajing; Chen, Yangpeng; Li, Mengke; Shi, Deyang; Wang, Bichen; Lian, Yu; Cheng, Xuelian; Wang, Xiaomin; Xu, Mingjiang; Cheng, Tao; Shi, Jun; Yuan, Weiping.

In: Cancer Science, Vol. 110, No. 7, 01.07.2019, p. 2200-2210.

Research output: Contribution to journalArticle

Chu, Y, Chen, Y, Li, M, Shi, D, Wang, B, Lian, Y, Cheng, X, Wang, X, Xu, M, Cheng, T, Shi, J & Yuan, W 2019, 'Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia', Cancer Science, vol. 110, no. 7, pp. 2200-2210. https://doi.org/10.1111/cas.14033
Chu Y, Chen Y, Li M, Shi D, Wang B, Lian Y et al. Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia. Cancer Science. 2019 Jul 1;110(7):2200-2210. https://doi.org/10.1111/cas.14033
Chu, Yajing ; Chen, Yangpeng ; Li, Mengke ; Shi, Deyang ; Wang, Bichen ; Lian, Yu ; Cheng, Xuelian ; Wang, Xiaomin ; Xu, Mingjiang ; Cheng, Tao ; Shi, Jun ; Yuan, Weiping. / Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia. In: Cancer Science. 2019 ; Vol. 110, No. 7. pp. 2200-2210.
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