PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential

Shia, Wei Jong; Okumura, Akiko; Yan, Ming; Sarkeshik, Ali; Lo, Miao Chia; Matsuura, Shinobu; Komeno, Yukiko; Zhao, Xinyang; Nimer, Stephen D.; Yates, John R.; Zhang, Dong Er

doi:10.1182/blood-2011-04-347476

Cited by 110 publications

(115 citation statements)

References 52 publications

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“…KLF4 increased expression of E2F2, which encodes a transcriptional regulator involved in hematopoietic stem cell self-renewal and differentiation (45). Conversely, KLF4 decreased expression of the oncogenes PRMT1 and BTK, which have known roles in leukemia (46,47). These changes were confirmed by RT-qPCR and Western blot analysis ( Fig.…”

Section: Klf4 Expression Is Decreased In Primary Patient Aml Casessupporting

confidence: 65%

“…As a transcriptional regulator, E2F2 regulates the balance of stem cell self-renewal and differentiation of erythrocytes (45), and it may also play a role in myeloid differentiation. KLF4 decreased expression of the oncogene PRMT1, whose knockdown reduces the growth and survival of leukemic cells (46). Lastly, KLF4 expression decreased BTK expression.…”

Section: Discussionmentioning

confidence: 99%

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Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Morris

Cummings

Korb

et al. 2016

Molecular and Cellular Biology

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bAcute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.A cute myeloid leukemia (AML) is characterized by increased self-renewal of leukemia stem or progenitor cells and a failure of differentiation to mature myeloid cells. Normal hematopoietic cell differentiation and proliferation are regulated by the expression and interaction of specific transcription factors (1, 2), which are altered in AML (3-5). Elucidation of the genomic landscape of AML has further highlighted that alterations in myeloid transcription factors play a significant role in leukemogenesis (4). Recent attention has focused on the role of aberrant expression of the Krüppel-like factor (KLF) family of transcription factors in cancer (5). This family includes 17 different isoforms that bind to GCrich regions of DNA via three zinc finger domains and regulate the transcriptional activity of target genes by using two glutaminerich transactivation domains (5). KLF4 regulates differentiation of epidermal and vascular smooth muscle cells (6, 7), as well as cellular reprogramming to induce pluripotent stem cells (8). In normal hematopoiesis, KLF2 and KLF4 regulate myeloid differentiation and KLF4 expression induces CDKN1A (p21), which contributes to cell cycle arrest (9-13). In T-cell acute lymphoblastic leukemia (T-ALL) (14) and B-cell lymphomas, KLF4 has been described as a tumor suppressor regulating proliferation, apoptosis, and differentiation (15). A recent study showed that the homeobox transcription factor CDX2 represses KLF4 in myeloid leukemia cells (16). The investigators also observed that C...

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Section: Klf4 Expression Is Decreased In Primary Patient Aml Casessupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Morris

Cummings

Korb

et al. 2016

Molecular and Cellular Biology

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“…11 On the other hand, AML1/ETO can also recruit coactivators (such as p300 and PRMT1) to activate genes, especially those involved in stem cell self-renewal, such as ID1, CDKN1A, and EGR1. 12,13 In addition to dynamic interactions with various regulatory (co)factors, a recent study has reported that AML1/ETO resides in and functions through a stable multiprotein complex that at least contains HEB, LYL1, LMO2, and CBFb, 14 providing another layer of regulatory complexity for AML1/ETO in regulating its target genes.…”

Section: Introductionmentioning

confidence: 99%

“…AML1/ETO has recently been reported to interact with p300 or PRMT1: both are essential for AML1/ETO-mediated gene activation and leukemogenesis. 12,13 Given the known modulatory effects of PRMT1 and p300 on AP-1-mediated regulation, 54,55 we assume that AP-1, p300, and PRMT1 may function together in the AML1/ETO-AML1 complex.…”

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confidence: 99%

Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia

Wang

et al. 2016

Blood

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Key Points• Wild-type AML1 and AML1/ ETO form a complex on chromatin via binding to adjacent different motifs and interacting through the runt homology domain.• The relative binding signals of AML1/ETO and AML1 and AP-1 recruitment determine whether AML1/ETO activates or represses its targets.The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. However, the genome-wide interplay between AML1/ETO and wild-type AML1 remains elusive in the leukemogenesis of t(8;21) AML. Through chromatin immunoprecipitation sequencing and computational analysis, followed by a series of experimental validations, we report here that wild-type AML1 is able to orchestrate the expression of AML1/ETO targets regardless of being activated or repressed; this is achieved via forming a complex with AML1/ETO and via recruiting the cofactor AP-1 on chromatin. On chromatin occupancy, AML1/ETO and wild-type AML1 largely overlap and preferentially bind to adjacent and distinct short and long AML1 motifs on the colocalized regions, respectively. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. These findings enrich our knowledge of understanding the significance of the interplay between the wild-type protein and the oncogenic fusion protein in the development of leukemia. (Blood. 2016;127(2):233-242) IntroductionMany oncogenic fusion proteins generated by chromosomal translocations play a causal role in the development of leukemia. The oncogenic lesion almost exclusively occurs in a single allele within an individual leukemia, whereas the wild-type protein produced from the nontranslocated allele generally still exists.1,2 The coexistence of the wild-type protein with the oncogenic fusion protein raises the question about their significance in leukemogenesis. To address this question, acute myeloid leukemia (AML) with the t(8;21) translocation and resultant AML1/ETO fusion gene is an ideal model, particularly through understanding the interplay between the AML1/ETO fusion protein and the AML1 wild-type protein.AML1 (also known as RUNX1 or core-binding factor a [CBFa]), a critical regulator of normal hematopoiesis, 3 is widely expressed in multiple hematopoietic lineages and regulates the expression of a variety of hematopoietic genes through recognizing the motif TGTGGT.4 AML1 is frequently involved in chromosomal abnormalities in AML, [5][6][7] among which AML1/ETO is the most common fusion protein resulted from the t(8;21) translocation. 7 Structurally, AML1/ETO consists of the N-terminal portion o...

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“…AE9a lacks the conserved ETO domains NHR3/4, whose interaction with corepressor proteins such as N-CoR/SMRT and HDACs is important for transcriptional repression (17)(18)(19)(20). Despite maintaining some corepressor interaction, AE9a has greatly diminished N-CoR and SMRT interaction and is a much less potent transcriptional repressor than full-length AE (17,(19)(20)(21)(22). The AML1-ETOtr mutant showed altered regulation of cell cycle proteins, thereby providing a proliferative advantage in K562 cells relative to AE (15).…”

mentioning

confidence: 99%

Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation

Link

Lin

Shrestha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34 + cord blood cells in longterm culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models.T he t(8;21)(q22;q22) chromosomal translocation comprises the N-terminal DNA binding domain of AML1 (RUNX1) and nearly the entire ETO (RUNX1T1) gene, forming the fusion protein AML1-ETO (AE) (1, 2). Conditional expression and transduction-transplantation approaches have demonstrated that expression of AE provides self-renewal signaling to hematopoietic stem/progenitor cells (HSPCs) but does not induce transformation in the absence of additional cooperating events (3-7). Several such cooperating events have been identified, including overexpression of WT1, mutant c-KIT, TEL-PDGFRB, FLT3-ITD, loss of p21, and treatment with the DNA-damaging agent ENU (6,(8)(9)(10)(11)(12)(13). Conversely, C-terminal truncation of AE through frameshift mutation (AML1-ETOtr) or alternative splicing at exon 9 (AE9a) leads to acute myeloid leukemia (AML) transformation of murine HSPCs (14, 15). The AE9a transcript is expressed in ∼70% of t(8;21) + AML patients, along with full-length AE (14, 16). AE9a lacks the conserved ETO domains NHR3/4, whose interaction with corepressor proteins such as N-CoR/SMRT and HDACs is important for transcriptional repression (17)(18)(19)(20). Despite maintaining some corepressor interaction, AE9a has greatly diminished N-CoR and SMRT interaction and is a much less potent transcriptional repressor than full-length AE (17,(19)(20)(21)(22). The AML1-ETOtr mutant showed altered regulation of cell cycle proteins, thereby providing a proliferative advantage in K562 cells relative to AE (15). Recently, DeKelver et al. showed that the interaction between N-CoR and the NHR4 domain plays an inhibitory role in leukemia development in the context of full-length AE (23). However, analysis of a small cohort of t(8;21) patient samples did not detect any mutations in the NHR4 domain, indicating that such mutations are probabl...

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PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential

Cited by 110 publications

References 52 publications

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia

Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation

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