Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development

Yan, Ming; Burel, Sebastien A.; Peterson, Luke F.; Kanbe, Eiki; Iwasaki, Hiromi; Boyapati, Anita; Hines, Robert; Akashi, Koichi; Zhang, Dong Er

doi:10.1073/pnas.0406702101

Cited by 109 publications

(134 citation statements)

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“…on April 3, 2019. by guest www.bloodjournal.org From JAK2, and STAT5 in EML-AE9a cells ( Figure 6C) and decreased phosphorylation of STAT3 and STAT5 in a primary AEtr leukemiaderived cell line ( Figure 6D). 19 Consistent with their effect on CD45 de-repression, the HDAC inhibitors TSA and VPA, and the DNA methyltransferase (DNMT) inhibitor DAC attenuated STAT3 and STAT5 activation on cytokine stimulation in SKNO-1 cells (supplemental Figure 7). …”

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confidence: 61%

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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confidence: 61%

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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“…However, this interpretation is complicated by the variety of truncated forms of RUNX1-ETO in Kasumi-1 cells, some of which are predicted to migrate only 5 kDa slower than RUNX1 (Yan et al, 2004). Therefore, we tested whether wildtype RUNX1 or ETO might also be sensitive to degradation in response to HDIs in human erythroleukemia (HEL) cells, which express easily detectable levels of RUNX1 and ETO.…”

Section: Runx1-eto Degradation In Response To Hdismentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

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“…Thus, AML1-ETO did not significantly alter expression of hELA2 following induction in U937 cells, nor did the induction of AML1-ETO expression correlate with a similar change in the expression levels of C/EBPa (Figure 6c). p21 Waf1/Cip1 was used as a control gene whose promoter is activated by AML1-ETO (Yan et al, 2004), which is readily detected by quantitative PCR (see Supplementary data) and by microarray analysis (T Berg and M Lu¨bbert, unpublished).…”

Section: Aml1-eto Does Not Repress Ela2 J Lausen Et Almentioning

confidence: 99%

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

et al. 2005

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A 117 bp fragment of the human ELA2 promoter has been characterized that can act as a minimal promoter for the expression of neutrophil elastase. Chromatin immunoprecipitation and siRNAs revealed that expression of ELA2 is regulated by the acute myeloid human leukemia 1 protein (AML1), C/EBPa, PU.1 and c-Myb transcription factors. ELA2 has also been investigated as a possible target of the leukemic fusion protein AML1-ETO resulting from the t(8;21) chromosomal translocation. AML1-ETO, like AML1, binds the ELA2 promoter in the myeloid cell lines Kasumi-1 and U937, but unexpectedly fails to significantly alter expression of ELA2. Although AML1-ETO downregulates the expression of C/EBPa, changes in C/EBPa expression do not correlate with changes in the expression of ELA2. Our observations indicate that AML1-ETO may not be a constitutive repressor of gene expression in every case in which it can associate with DNA, either on its own or in conjunction with C/EBPa. Since neither ETO nor AML1-ETO are typically expressed in hematopoietic progenitors, we hypothesize that it is the interactions between AML1-ETO and regulatory cofactors in disease-state cells that alter gene expression programs during hematopoiesis. These protein-protein interactions may not require simultaneous DNA binding by AML1-ETO for the deleterious effects of the fusion protein to be realized.

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Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development

Cited by 109 publications

References 56 publications

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

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

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

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