<i>PBX3</i> is essential for leukemia stem cell maintenance in <i>MLL</i>‐rearranged leukemia

Guo, Huibin; Chu, Yajing; Wang, Le; Chen, Xing; Chen, Yangpeng; Cheng, Hui; Zhang, Lei; Zhou, Yuan; Yang, Feng Chun; Cheng, Tao; Xu, Mingjiang; Zhang, Xiaobing; Zhou, Jianfeng; Yuan, Weiping

doi:10.1002/ijc.30739

Cited by 34 publications

(30 citation statements)

References 45 publications

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“…In particular, PBX3 serves a critical role in the development of MLL-rearranged AML. The cooperation of HOXA9 with PBX3 is needed for cell transformation and leukemogenesis 16 , 17 . However, whether HOXA and PBX3 are essential for NPMc+ leukemic cell survival is unknown.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival

Zhang

Zhao

et al. 2018

Theranostics

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Acute myeloid leukemia (AML) with an NPM1 mutation (NPMc+) has a distinct gene expression signature and displays molecular abnormalities similar to mixed lineage leukemia (MLL), including aberrant expression of the PBX3 and HOXA gene cluster. However, it is unclear if the aberrant expression of PBX3 and HOXA is essential for the survival of NPM1-mutated leukemic cells.Methods: Using the gene expression profiling of TCGA and E-MTAB-3444 datasets, we screened for high co-expression of PBX3 and HOXA9 in NPMc+ leukemia patients. We performed NPMc+ depletion and overexpression experiments to examine aberrant H3K79 methylation through epigenetic regulation. Through RNA interference technology and small-molecule inhibitor treatment, we evaluated the effect of methyl-modified H3K79 on cell survival and explored the possible underlying mechanism.Results: We showed that NPMc+ increased the expression of PBX3 and HOXA9, which are both poor prognosis indicators in AML. High PBX3 and HOXA9 expression was accompanied by increased dimethylated and trimethylated H3K79 in transgenic murine Lin-Sca-1+c-Kit+ cells and human NPMc+ leukemia cells. Using chromatin immunoprecipitation sequencing (ChIP-seq) assays of NPMc+ cells, we determined that hypermethylated H3K79 was present at the expressed HOXA9 gene but not the PBX3 gene. PBX3 expression was positively regulated by HOXA9, and a reduction in either PBX3 or HOXA9 resulted in NPMc+ cell apoptosis. Importantly, an inhibitor of DOT1L, EPZ5676, effectively and selectively promoted NPMc+ human leukemic cell apoptosis by reducing HOXA9 and PBX3 expression.Conclusion: Our data indicate that NPMc+ leukemic cell survival requires upregulation of PBX3 and HOXA9, and this action can be largely attenuated by a DOT1L inhibitor.

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Section: Introductionmentioning

confidence: 99%

Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival

Zhang

Zhao

et al. 2018

Theranostics

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“…deregulated transcription of HoXa members (HoXa5, HOXA9 and HOXA10) has been identified as a hallmark of Mll rearrangement leukemia (30)(31)(32). it was demonstrated that induced expression of PBX homeobox 3 was sufficient for malignant transformation of normal mouse hematopoietic stem/progenitor cells (33,34). Sestrin 3 has been reported to repress ribosomal protein S6 kinase (S6K1) activity by reducing its phosphorylation, which affected the mechanistic target of rapamycin kinase pathway and suppressed leukemic progenitor colony formation in breakpoint cluster region-aBl proto-oncogene 1, non-receptor tyrosine kinase leukemia cell lines (35).…”

Section: Discussionmentioning

confidence: 99%

Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemia with MLL‑AF9 translocation

Wang

et al. 2019

Mol Med Report

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rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (aMl). MLLT3, super elongation complex subunit (AF9) is one of the most common Mll fusion partners in aMl. The present study aimed to explore the aberrant expression of genes associated with the MLL-AF9 translocation and identified potential new targets for the therapy of aMl with Mll-aF9 translocation. The transcriptomic and epigenetic datasets were downloaded from national center of Biotechnology information Gene expression omnibus (Geo) database. differentially expressed genes were obtained from two independent datasets (GSe68643 and GSe73457). Gene ontology biological process and Kyoto encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the database for annotation, Visualization and integrated discovery. Mll-aF9-associated chromatin immunoprecipitation sequencing (ChIP-Seq) data was analyzed and identified binding sites for Mll-aF9 and wild type Mll (Mll WT). The chiP-Seq of histone modification data was downloaded from the Geo database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the Mll-aF9 leukemia cells and normal hematopoietic cells at Mll-aF9 and Mll WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL-AF9 direct target genes. upon validation using rna-Seq data from the Therapeutically applicable research to Generate effective Treatments aMl project, eight potential direct target genes of MLL-AF9 were identified and further confirmed in MLL-AF9 mouse model using reverse transcription-quantitative polymerase chain reaction. These genes may have a critical role in aMl with Mll-aF9 translocation.

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“…All animal research was approved by the Institutional Animal Care and Use Committee of SKLEH. MLL‐AF9 or MLL‐NRIP3 leukemic mice were generated by transplantation of leukemia cells carrying MLL‐AF9 or MLL‐NRIP3 fusion genes into sub‐lethally irradiated (4 Gy) mice, respectively. MLL‐NRIP3 (MN3) is a recently reported MLL translocation and was demonstrated to be able to induce AML in mice in previous studies …”

Section: Methodsmentioning

confidence: 99%

“…Bone marrow cells were flushed with 2 mmol/L EDTA and 2% FBS containing PBS and were then stained with antibodies at the appropriate proper dilution (Table ). Flow cytometric analysis of c‐Kit + or L‐GMP (Lin − c‐Kit + IL‐7R − Sca‐1 − CD16/32 + CD34 + ) cells was performed as previously described . For L‐GMP, the lineage cocktail (Lin) contains Gr‐1, Ter119, B220, CD3, CD4 and CD8.…”

Section: Methodsmentioning

confidence: 99%

“…Flow cytometric analysis of c-Kit + or L-GMP (Lin − c-Kit + IL-7R − Sca-1 − CD16/32 + CD34 + ) cells was performed as previously described. 32 For L-GMP, the lineage cocktail (Lin) contains Gr-1, Ter119, B220, CD3, CD4 and CD8. The analyses were performed using a BD Canto II or LSR Fortessa flow cytometer (BD Biosciences, San Jose, CA, USA).…”

Section: Flow Cytometry Apoptosis and Cell Cycle Analysismentioning

confidence: 99%

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Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Chu

Chen

et al. 2019

Cancer Science

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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.

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PBX3 is essential for leukemia stem cell maintenance in MLL‐rearranged leukemia

Cited by 34 publications

References 45 publications

Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival

Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival

Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemia with MLL‑AF9 translocation

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

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