The Leukemogenicity of AML1-ETO Is Dependent on Site-Specific Lysine Acetylation

Wang, Lan; Gural, Alexander; Sun, Xiao Jian; Zhao, Xinyang; Perna, Fabiana; Huang, Gang; Hatlen, Megan A.; Vu, Ly; Liu, Fan; Xu, Huiling; Asai, Takashi; Hu, Xu; DeBlasio, Tony; Menéndez, Sílvia; Voza, Francesca; Jiang, Yanwen; Cole, Philip A.; Zhang, Jinsong; Melnick, Ari; Roeder, Robert G.; Nimer, Stephen D.

doi:10.1126/science.1201662

Cited by 214 publications

(241 citation statements)

References 29 publications

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“…The significance of this observation to this study is that RUNX1 is an important upstream activator of the SPI1 gene in humans and the Sfpi1 gene in mice (56). PU.1 levels are reduced upon expression of RUNX1 fusion proteins such as ETO-RUNX1 (57,58). Recently, it was also shown that B-ALL cells harboring ETV6-RUNX1 fusions express reduced levels of Spi-B (14).…”

Section: Discussionmentioning

confidence: 88%

Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

Sokalski

Hotke

et al. 2012

The Journal of Immunology

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B cell acute lymphoblastic leukemia (B-ALL) is frequently associated with mutations or chromosomal translocations of genes encoding transcription factors. Conditional deletion of genes encoding the E26-transformation–specific transcription factors, PU.1 and Spi-B, in B cells (ΔPB mice) leads to B-ALL in mice at 100% incidence rate and with a median survival of 21 wk. We hypothesized that PU.1 and Spi-B may redundantly activate transcription of genes encoding tumor suppressors in the B cell lineage. Characterization of aging ΔPB mice showed that leukemia cells expressing IL-7R were found in enlarged thymuses. IL-7R–expressing B-ALL cells grew in culture in response to IL-7 and could be maintained as cell lines. Cultured ΔPB cells expressed reduced levels of B cell linker protein (BLNK), a known tumor suppressor gene, compared with controls. The Blnk promoter contained a predicted PU.1 and/or Spi-B binding site that was required for promoter activity and occupied by PU.1 and/or Spi-B as determined by chromatin immunoprecipitation. Restoration of BLNK expression in cultured ΔPB cells opposed IL-7–dependent proliferation and induced early apoptosis. We conclude that the tumor suppressor BLNK is a target of transcriptional activation by PU.1 and Spi-B in the B cell lineage.

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Section: Discussionmentioning

confidence: 88%

Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

Sokalski

Hotke

et al. 2012

The Journal of Immunology

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“…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.…”

Section: Introductionmentioning

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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“…6 Furthermore, C646 can selectively induce cell death in leukemia cells containing the AML-ETO gene fusion, which encodes a transcription factor whose activity is dependent on p300/CBP KAT function. 7,8 Recently there has been an increased interest in understanding the mechanisms and liabilities of pan-assay interference compounds (commonly referred to as PAINS).…”

mentioning

confidence: 99%

Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300

Shrimp

Sorum

Garlick

et al. 2015

ACS Med. Chem. Lett.

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C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and synthetic derivatization was used to develop a clickable analogue (C646-yne) that inhibits p300 similarly to the parent compound and enables enrichment of bound proteins. LC−MS/MS identified the major covalent targets of C646-yne as highly abundant cysteine-containing proteins, and follow-up studies found that C646 can inhibit tubulin polymerization in vitro. Finally, we provide evidence that thiol reactivity of C646 may limit its ability to antagonize acetylation in cells. These findings should enable a more precise interpretation of studies utilizing C646 as a chemical probe of KAT activity and suggest that an underappreciated liability of electrophile-containing inhibitors is a reduction in their cellular potency due to consumption by abundant protein and metabolite thiol sinks.

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The Leukemogenicity of AML1-ETO Is Dependent on Site-Specific Lysine Acetylation

Cited by 214 publications

References 29 publications

Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

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

Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300

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