Transcriptional dysregulation mediated by RUNX1-RUNX1T1 in normal human progenitor cells and in acute myeloid leukaemia

Tonks, Alex; Pearn, Lorna; Musson, Megan; Gilkes, Amanda F.; Mills, Ken I.; Burnett, Alan Kenneth; Darley, Richard Lawrence

doi:10.1038/sj.leu.2404961

Cited by 78 publications

(89 citation statements)

References 56 publications

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“…Lineage promiscuity in t(8;21) AML K Walter et al human CD34 þ cells showed neither PAX5 upregulation nor CD19 expression (Mulloy et al, 2005;Tonks et al, 2007). In addition, AML cells from conditional RUNX1/RUNX1T1 transgenic mice do not express CD19 (data not shown).…”

Section: Discussionmentioning

confidence: 90%

“…As a result, the RUNX1-RUNX1T1 fusion protein can recruit transcriptional co-repressor complexes to RUNX1 binding sites and thus represses RUNX1 target genes (Linggi et al, 2002;Follows et al, 2003). However, ectopic expression of RUNX1-RUNX1T1 in human CD34 þ hematopoietic precursor cells induces both the upregulation and downregulation of a number of genes (Mulloy et al, 2005;Tonks et al, 2007), indicating that the expression of this oncoprotein disturbs the entire myeloid gene regulatory network. This widespread dysregulation does not only affect myeloid-specific genes.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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“…Expression of 1045 genes were dysregulated Ն 1.5-fold in AE9a LK cells, with 337 up-regulated and 486 down-regulated by at least 2-fold (P Ͻ .001, 2-sample t test; supplemental Table 1). Among these genes, 195 were also found to be dysregulated in AML1-ETO-transduced human hematopoietic cells [30][31][32] or t(8;21) AML blasts 33,34 (supplemental Table 2). Among the up-regulated genes are positive cell-cycle regulators, such as Ccnb1, Ccnd2, and Cdc25b.…”

Section: Gene Expression and Promoter Occupancy Profiling Of Primary mentioning

confidence: 99%

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Peterson

Yan

et al. 2012

Blood

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IntroductionAcute myeloid leukemia (AML) is a common hematologic malignancy characterized by an abnormal accumulation of myeloid precursors in the bone marrow and blood. Similar to many other types of cancer, genetic abnormalities are associated with the development of AML, particularly chromosomal translocations that result in novel fusion proteins. One of the common translocations implicated in AML is the 8q22;21q22 translocation [t(8;21)]. 1 Based on the French-American-British (FAB) classification of leukemic cells, t(8;21) is associated with nearly 40% of the AML cases with the FAB M2 phenotype. 2 t(8,21) involves the AML1 (RUNX1) gene on chromosome 21 and the ETO (MTG8, RUNX1T1) gene on chromosome 8. [3][4][5] AML1 is the DNA-binding subunit of the core binding factor (CBF) transcription factor complex. Its N-terminus contains a highly conserved DNA binding domain called the runt homology domain (RHD). t(8;21) fuses the N-terminus of AML1 including RHD in-frame with almost the entire ETO protein to form AML1-ETO. [3][4][5][6] This fusion protein acts as a dominant negative form of AML1 during embryogenesis. 7,8 It functions as a transcriptional repressor by interacting with NCoR/SMRT/HDAC. 9,10 AML1-ETO was shown to activate expression of BCL-2 and p21, possibly via interacting with p300. [11][12][13] AML1-ETO promotes stem cell renewal and blocks hematopoietic differentiation. [14][15][16] However, its role in blocking cell-cycle progression and promoting apoptosis contradicts its function in promoting leukemogenesis and therefore requires secondary mutagenic events for full transformation. 17,18 We previously identified a single nucleotide insertion that resulted in a truncated AML1-ETO protein (AML1-ETOtr or AEtr), which rapidly promoted leukemia. 19 Subsequently, we identified a C-terminally truncated variant of AML1-ETO named AML1-ETO9a (AE9a), resulting from alternative splicing and found to coexist with full-length AML1-ETO in most analyzed t(8;21) AML patients. 20 Similar to AEtr, AE9a causes a rapid onset of leukemia in mice, 20 which provides a useful mouse model to study the molecular biology of t(8;21) leukemia.To understand the molecular mechanism of AML1-ETOrelated leukemia development and to explore novel therapeutic targets to treat this type of leukemia, in this study we combined gene expression microarray and promoter occupancy (ChIP-chip) analyses to identify genes directly modulated by AE9a in primary murine leukemia cells. Among the common targets of microarray and ChIP-chip assays, approximately 30% show human t(8;21)-specific up or down-regulation compared with AML that have other chromosomal abnormalities. CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, 21-23 is among those targets. Its expression is down-regulated in AE9a leukemia cells. Consequently, JAK/STAT signaling is enhanced in these leukemia cells. We show that re-expression of CD45 suppresses JAK/STAT activation, delays leukemia development by AE9a an...

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“…The following publicly available gene expression databases were used: http: //www.genecards.org, 56 http: //www.ebi.ac.uk/arrayexpress/ (for example, experiment E-MEXP-583) 57,58 and http://www.biogps.gnf.org.…”

Section: Online Resourcesmentioning

confidence: 99%

Physiological regulation of transgene expression by a lentiviral vector containing the A2UCOE linked to a myeloid promoter

et al. 2011

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Protection against epigenetic silencing is a desirable feature of future gene therapy vectors, in particular for those applications in which transgene expression will not confer growth advantage to gene-transduced cells. The ubiquitous chromatin opening element (UCOE) consisting of the methylation-free CpG island encompassing the dual divergently transcribed promoters of the human HNRPA2B1-CBX3 housekeeping genes (A2UCOE) has been shown to shield constitutive active heterologous promoters from epigenetic modifications and chromosomal position effects. However, it is unclear if this element can be used to improve expression from tissue-specific enhancer/promoters, while maintaining tissue specificity in hematopoietic cells. Here, we evaluated the potential of the A2UCOE in combination with the myeloid-specific myeloid related protein 8 (MRP8) promoter to target transgene expression specifically to myeloid cells in vitro and in vivo from a self-inactivating lentiviral vector. The inclusion of the A2UCOE did not interfere with specific upregulation of MRP8 promoter activity during myeloid differentiation and mediated sustained and vector copy-dependent expression in myeloid cells. Notably, the A2UCOE did not protect the MRP8 promoter from methylation in the P19 embryonal carcinoma cell line, suggesting that this element maintains the inherent epigenetic state and transcriptional activity of cellular promoters in their native configuration. Thus, the A2UCOE could represent a useful protective genetic element in gene therapy vectors, ensuring physiological transcriptional regulation of tissue-specific promoters independent of the chromosomal integration site.

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Transcriptional dysregulation mediated by RUNX1-RUNX1T1 in normal human progenitor cells and in acute myeloid leukaemia

Cited by 78 publications

References 56 publications

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Physiological regulation of transgene expression by a lentiviral vector containing the A2UCOE linked to a myeloid promoter

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