<i>Six1</i> regulates leukemia stem cell maintenance in acute myeloid leukemia

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

doi:10.1111/cas.14033

Cited by 21 publications

(17 citation statements)

References 66 publications

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“… 16 , 37 , 40 Interestingly, Six1 was recently shown to be important for leukemic stem cell maintenance where depletion of Six1 leads to increased disease latency. 47 This suggests repression of Six1 may contribute to SETDB1 mediated extension of leukemic disease latency. These data point to SETDB1 negatively regulating a pro-leukemic gene program, many of which are potential therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

Ropa¹,

Saha²,

Hu³

et al. 2019

haematol

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Epigenetic regulators play a critical role in normal and malignant hematopoiesis. Deregulation, including epigenetic deregulation, of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia. We recently showed that the Histone 3 Lysine 9 methyltransferase SETDB1 negatively regulates the expression of the pro-leukemic genes Hoxa9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation in MLL-AF9 leukemia cells. Here, we investigated the biological impact of altered SETDB1 expression and changes in H3K9 methylation on acute myeloid leukemia. We demonstrate that SETDB1 expression is correlated to disease status and overall survival in acute myeloid leukemia patients. We recapitulated these findings in mice, where high expression of SETDB1 delayed MLL-AF9 mediated disease progression by promoting differentiation of leukemia cells. We also explored the biological impact of treating normal and malignant hematopoietic cells with an H3K9 methyltransferase inhibitor, UNC0638. While myeloid leukemia cells demonstrate cytotoxicity to UNC0638 treatment, normal bone marrow cells exhibit an expansion of cKit+ hematopoietic stem and progenitor cells. Consistent with these data, we show that bone marrow treated with UNC0638 is more amenable to transformation by MLL-AF9. Next generation sequencing of leukemia cells shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with acute myeloid leukemia, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in leukemia that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing acute myeloid leukemia.

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Section: Discussionmentioning

confidence: 99%

SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

Ropa¹,

Saha²,

Hu³

et al. 2019

haematol

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“…Indeed, Eya1 overexpression immortalizes hematopoietic progenitor cells, and heterodimerization with Six1 augments this effect (26). Furthermore, two recent reports demonstrate a reduced LIC population in Six1 knockout or knockdown mouse cells expressing MLL-AF9 versus in a Six1 WT background (48,49). The unexpected observation that we see increased proliferation in the colony formation assay with MLL-AF9(E531R) could in part be due to increased expression of Hoxa7 ( Fig.…”

Section: Discussionmentioning

confidence: 52%

BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity

Schmidt

Kuntimaddi

Boulton

et al. 2020

Blood Cancer Discovery

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MLL is a target of chromosomal translocations in acute leukemias with poor prognosis. The common MLL fusion partner AF9 (MLLT3) can directly bind to AF4, DOT1L, BCOR, and CBX8. To delineate the relevance of BCOR and CBX8 binding to MLL-AF9 for leukemogenesis, here we determine protein structures of AF9 complexes with CBX8 and BCOR, and show that binding of all four partners to AF9 is mutually exclusive. Using the structural analyses, we identify point mutations that selectively disrupt AF9 interactions with BCOR and CBX8. In bone marrow stem/progenitor cells expressing point mutant CBX8 or point mutant MLL-AF9, we show that disruption of direct CBX8/MLL-AF9 binding does not impact in vitro cell proliferation, whereas loss of direct BCOR/MLL-AF9 binding causes partial differentiation and increased proliferation. Strikingly, loss of MLL-AF9/BCOR binding abrogated its leukemogenic potential in a mouse model. The MLL-AF9 mutant deficient for BCOR binding reduces the expression of the EYA1 phosphatase and the protein level of c-Myc. Reduction in BCOR binding to MLL-AF9 alters a MYC-driven gene expression program, as well as altering expression of SIX-regulated genes, likely contributing to the observed reduction in the leukemia-initiating cell population. Significance: Direct recruitment of BCOR to MLL-AF9 is essential for leukemia via EYA1 phosphatase regulation, altering MYC and SIX gene expression programs. Specific partner binding (AF4, DOT1L, and BCOR) contributes in distinct ways to MLL leukemia. This may provide a rationale for combination DOT1L and EYA1 inhibition for MLL fusion leukemia treatment. This article is highlighted in the In This Issue feature, p. 127

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“…PAX6 is a key member of the retinal determination gene network (RDGN), which is a conservative pathway required for the development of a number of organs in mammals, including eyes, pancreas and central nervous system (11,12). Recent studies have indicated that aberrant expression of RDGN members is involved in cancer initiation and progression (13)(14)(15)(16)(17). Indeed, PAX6 is overexpressed in various types of human cancers, which suggests its oncogenic roles (7,(18)(19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Possible involvement of TGF‑β‑SMAD‑mediated epithelial‑mesenchymal transition in pro‑metastatic property of PAX6

et al. 2020

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Paired box 6 (PAX6) is a transcription factor that has oncogenic features. In breast cancer, PAX6 facilitates tumor progression; however, the underlying mechanism is largely unknown. The majority of breast cancer-related mortalities are associated with metastasis of cancer cells. Therefore, the present study aimed to investigate the role of PAX6 in breast tumor metastasis. PAX6 was stably overexpressed in breast cancer cells to perform tumor migration and metastasis assays in vitro and in vivo. In addition, the expression of PAX6 and transforming growth factor β (TGF-β)-SMAD signaling associated proteins on human breast cancer tissue array, as well as key factors involved in epithelial-mesenchymal transition (EMT) were assayed to explore the mechanism underlying metastasis of breast cancer cells. The expression levels of PAX6 were demonstrated to be increased in human breast cancer tissues and associated with poor clinical outcomes. Overexpression of PAX6 markedly promoted metastasis. Further investigation revealed that PAX6 overexpression increased TGF-β-SMAD signaling pathway and induced EMT. These results suggested that highly expressed PAX6 led to EMT through TGF-β-SMAD signaling pathway, thereby promoting cell metastasis and ultimately affecting survival in patients with breast cancer. Taken together, findings indicated that PAX6 may serve as a therapeutic target for the clinical treatment of breast cancer and the underlying mechanism could be used to overcome metastasis of cancer cells.

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Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Cited by 21 publications

References 66 publications

SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity

Possible involvement of TGF‑β‑SMAD‑mediated epithelial‑mesenchymal transition in pro‑metastatic property of PAX6

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