Hydrogen-Induced Formation of Surface Acid Sites on Pt/Al(PO3)3 Enables Remarkably Efficient Hydrogenolysis of C-O Bonds in Alcohols and Ethers.

The hydrogenolysis of oxygenates such as alcohols and ethers is central to the biomass valorization and also a valuable transformation in organic synthesis. However, a mild and efficient catalyst system for the hydrogenolysis of a large variety of alcohols and ethers with various functional groups is still underdeveloped. Here, we report an aluminum metaphosphate-supported Pt nanoparticles (Pt/Al(PO3)3) for the hydrogenolysis of a wide variety of primary, secondary, and tertiary alkyl and benzylic alcohols, and dialkyl, aryl alkyl, and diaryl ethers, including biomass-derived furanic compounds, under mild conditions (0.1-1 atm of H2, as low as 70 °C). Mechanistic studies suggested that H2 induces formation of the surface Brønsted acid sites via its cleavage by supported Pt nanoparticles. Accordingly, the high efficiency and the wide applicability of the catalyst system are attributed to the activation and cleavage of C-O bonds by the hydrogen-induced Brønsted acid sites with the assistance of Lewis acidic Al sites on the catalyst surface. The high efficiency of the catalyst implies its potential application in energy-efficient biomass valorization or fine chemical synthesis.

HEY1-NCOA2 expression modulates chondrogenic differentiation and induces mesenchymal chondrosarcoma in mice.

Mesenchymal chondrosarcoma affects adolescents and young adults, and most cases usually have the HEY1::NCOA2 fusion gene. However, the functional role of HEY1-NCOA2 in the development and progression of mesenchymal chondrosarcoma remains largely unknown. This study aimed to clarify the functional role of HEY1-NCOA2 in transformation of the cell of origin and induction of typical biphasic morphology of mesenchymal chondrosarcoma. We generated a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic superficial zone (eSZ) followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression in eSZ cells successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation. ChIP sequencing analyses indicated frequent interaction between HEY1-NCOA2 binding peaks and active enhancers. Runx2, which is important for differentiation and proliferation of the chondrocytic lineage, is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. Although Runx2 knockout resulted in significant delay in tumor onset, it also induced aggressive growth of immature small round cells. Runx3, which is also expressed in mesenchymal chondrosarcoma and interacts with HEY1-NCOA2, replaced the DNA-binding property of Runx2 only in part. Treatment with the HDAC inhibitor panobinostat suppressed tumor growth both in vitro and in vivo, abrogating expression of genes downstream of HEY1-NCOA2 and Runx2. In conclusion, HEY1::NCOA2 expression modulates the transcriptional program in chondrogenic differentiation, affecting cartilage-specific transcription factor functions.

ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a soft part malignancy affecting adolescents and young adults. ASPS is characterized by a highly integrated vascular network, and its high metastatic potential indicates the importance of ASPS's prominent angiogenic activity. Here, we find that the expression of ASPSCR1::TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance; however, it is required for in vivo tumor development via angiogenesis. ASPSCR1::TFE3 is frequently associated with super-enhancers (SEs) upon its DNA binding, and the loss of its expression induces SE-distribution dynamic modification related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical targets associated with reduced enhancer activities due to the ASPSCR1::TFE3 loss. Upregulation of Rab27a and Sytl2 promotes angiogenic factor-trafficking to facilitate ASPS vascular network construction. ASPSCR1::TFE3 thus orchestrates higher ordered angiogenesis via modulating the SE activity.

Multifunctional WO3-ZrO2-Supported Platinum Catalyst for Remarkably Efficient Hydrogenolysis of Esters to Alkanes.

The hydrogenolysis of esters to alkanes is a key protocol for the synthesis of high-quality hydrocarbon fuels from renewable plant oils or fats. However, performing this process under mild energy-efficient conditions is challenging. Herein, we report a robust tungsten- and zirconium-oxide-supported platinum catalyst (Pt/WO3-ZrO2) for the hydrogenolysis of esters to alkanes at low temperatures (as low as 70 °C) and under ambient pressure (1 atm) of H2. For example, tristearin undergoes a complete conversion at 130 °C with more than 95% selectivity for the corresponding alkanes without carbon loss. In addition, the heterogeneous nature of the catalyst system reported herein permits multiple reuse of the catalyst without any significant loss of its high activity and selectivity. Mechanistic studies suggest that the multifunctional nature (acid and redox properties) of the WO3-ZrO2 support plays an important role in the high activity of the catalyst.

Crystal Facet Engineering and Hydrogen Spillover-Assisted Synthesis of Defective Pt/TiO2-x Nanorods with Enhanced Visible Light-Driven Photocatalytic Activity.

Hydrogen spillover can assist the introduction of defects such as Ti3+ and concomitant oxygen vacancies (VO) in a TiO2 crystal, thereby inducing a new level below the conduction band to improve the conductivity of photogenerated electrons and the visible light absorption property of TiO2. Meanwhile, crystal facet engineering offers a promising approach to achieve improved activity by influencing the recombination step of the photogenerated electrons and holes. In this study, with the aim of achieving enhanced visible light-driven photocatalytic activity, rutile TiO2 nanorods with different aspect ratios were synthesized by crystal facet engineering, and Pt-deposited TiO2-x nanorods (Pt/TNR) were then obtained via reduction treatment assisted by hydrogen spillover. The reduction treatment at 200 °C induced the formation of surface Ti3+ exclusively, whereas surface Ti3+ and VO were formed by performing the reduction at 600 °C. The Pt/TNR with a higher aspect ratio reduced at 200 °C exhibited the highest activity in photocatalytic H2 production under visible light irradiation owing to the synergistic effect of the introduction of Ti3+ defects and the spatial charge carrier separation induced by crystal facet engineering.

BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes.

The transcriptional repressor BCL11A is involved in hematological malignancies, B-cell development, and fetal-to-adult hemoglobin switching. However, the molecular mechanism by which it promotes the development of myeloid leukemia remains largely unknown. We find that Bcl11a cooperates with the pseudokinase Trib1 in the development of acute myeloid leukemia (AML). Bcl11a promotes the proliferation and engraftment of Trib1-expressing AML cells in vitro and in vivo. Chromatin immunoprecipitation sequencing analysis showed that, upon DNA binding, Bcl11a is significantly associated with PU.1, an inducer of myeloid differentiation, and that Bcl11a represses several PU.1 target genes, such as Asb2, Clec5a, and Fcgr3. Asb2, as a Bcl11a target gene that modulates cytoskeleton and cell-cell interaction, plays a key role in Bcl11a-induced malignant progression. The repression of PU.1 target genes by Bcl11a is achieved by sequence-specific DNA-binding activity and recruitment of corepressors by Bcl11a. Suppression of the corepressor components HDAC and LSD1 reverses the repressive activity. Moreover, treatment of AML cells with the HDAC inhibitor pracinostat and the LSD1 inhibitor GSK2879552 resulted in growth inhibition in vitro and in vivo. High BCL11A expression is associated with worse prognosis in humans with AML. Blocking of BCL11A expression upregulates the expression of PU.1 target genes and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity.

One-Pot Synthesis of Long Rutile TiO2 Nanorods and Their Photocatalytic Activity for O2 Evolution: Comparison with Near-Spherical Nanoparticles.

Rutile TiO2 nanorods with lengths greater than 600 nm and aspect ratios greater than ca. 16 were synthesized through a one-pot hydrothermal method using lactic acid (LA) as a structure-directing agent. Under the hydrothermal treatment at 200 °C, the LA concentration higher than 1.6 mol dm-3 and the hydrothermal time of 72 h were needed to obtain 100% rutile nanorods. The length and the width of the nanorods increased with the increasing LA concentration. The photocatalytic activity of the synthesized nanorods was evaluated for the oxygen evolution in aqueous AgNO3 solutions under ultraviolet irradiation. Calcination of the synthesized nanorods at 400 °C was required to decompose residual organic compounds on the surface and improve the oxygen evolution. The highest oxygen evolution rate was obtained with the nanorods after being calcined at 800 °C. It is worth noting that the nanorods retained their shape (aspect ratio of 8.8) at 800 °C. Selected area electron diffraction patterns indicated that the side or the end surface of the nanorods was attributable to the {110} or {111} facet, respectively. Deposition of Pt or PbO2 on the nanorods revealed that the {110} or {111} facet acted as reductive or oxidative sites. For comparison, near-spherical TiO2 nanoparticles were synthesized by a sol-gel method. Furthermore, using glycolic acid as the structure-directing agent, we synthesized small rutile TiO2 nanorods (aspect ratio of 9) and changed the shape to near-spherical (aspect ratio of 1.3) by calcining at 800 °C. Time-resolved diffuse reflectance spectra were measured to determine the lifetime of the photogenerated electrons. The photocatalytic activity of the nanorods was much lower than that of the near-spherical TiO2 nanoparticles. However, the nanorods synthesized with LA are useful as catalyst support or platforms for various applications because of their unique morphology and high heat resistance.

C/EBPß induces B-cell acute lymphoblastic leukemia and cooperates with BLNK mutations.

BLNK (BASH/SLP-65) encodes an adaptor protein that plays an important role in B-cell receptor (BCR) signaling. Loss-of-function mutations in this gene are observed in human pre-B acute lymphoblastic leukemia (ALL), and a subset of Blnk knock-out (KO) mice develop pre-B-ALL. To understand the molecular mechanism of the Blnk mutation-associated pre-B-ALL development, retroviral tagging was applied to KO mice using the Moloney murine leukemia virus (MoMLV). The Blnk mutation that significantly accelerated the onset of MoMLV-induced leukemia and increased the incidence of pre-B-ALL Cebpb was identified as a frequent site of retroviral integration, suggesting that its upregulation cooperates with Blnk mutations. Transgenic expression of the liver-enriched activator protein (LAP) isoform of Cebpb reduced the number of mature B-lymphocytes in the bone marrow and inhibited differentiation at the pre-BI stage. Furthermore, LAP expression significantly accelerated leukemogenesis in Blnk KO mice and alone acted as a B-cell oncogene. Furthermore, an inverse relationship between BLNK and C/EBPß expression was also noted in human pre-B-ALL cases, and the high level of CEBPB expression was associated with short survival periods in patients with BLNK-downregulated pre-B-ALL. These results indicate the association between the C/EBPß transcriptional network and BCR signaling in pre-B-ALL development and leukemogenesis. This study gives insight into ALL progression and suggests that the BCR/C/EBPß pathway can be a therapeutic target.

Defect Engineering of Pt/TiO2-x Photocatalysts via Reduction Treatment Assisted by Hydrogen Spillover.

Defect engineering of metal oxides is a facile and promising strategy to improve their photocatalytic activity. In the present study, Pt/TiO2-x was prepared by a reduction treatment assisted by hydrogen spillover to pure rutile, anatase, and brookite and was subsequently used for hydrogen production from an aqueous methanol solution. With increasing reduction temperature, the photocatalytic activity of the rutile Pt/TiO2-x increased substantially, whereas the activity of anatase Pt/TiO2-x decreased and that of brookite Pt/TiO2-x was independent of the treatment temperature. Electron-spin resonance analysis revealed that rutile and brookite possess similar defect sites (Ti3+ and concomitant oxygen vacancy) after the reduction at 600 °C, whereas different resonance signals were observed for anatase after the reduction at 600 °C. During the reduction process, electrons donated from spillover hydrogen migrate between the conduction band and the inherent midgap states. This research demonstrates that the depth of the inherent midgap states, depending on the crystal phases, influences the generation of defects, which play a key role in the photocatalytic performance of Pt/TiO2-x.

Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9.

The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPα and interacts with MEK1 to enhance extracellular signal-regulated kinase (ERK) phosphorylation. A close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis, where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. Chromatin immunoprecipitation sequencing analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased messenger RNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPα p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model.

Fusion genes induced by chromosomal aberrations are common mutations causally associated with bone and soft tissue sarcomas (BSTS). These fusions are usually disease type-specific, and identification of the fusion genes greatly helps in making precise diagnoses and determining therapeutic directions. However, there are limitations in detecting unknown fusion genes or rare fusion variants when using standard fusion gene detection techniques, such as reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). In the present study, we have identified 19 novel fusion genes using target RNA sequencing (RNA-seq) in 55 cases of round or spindle cell sarcomas in which no fusion genes were detected by RT-PCR. Subsequent analysis using Sanger sequencing confirmed that seven out of 19 novel fusion genes would produce functional fusion proteins. Seven fusion genes detected in this study affect signal transduction and are ideal targets of small molecule inhibitors. YWHAE-NTRK3 expression in mouse embryonic mesenchymal cells (eMCs) induced spindle cell sarcoma, and the tumor was sensitive to the TRK inhibitor LOXO-101 both in vitro and in vivo. The combination of target RNA-seq and generation of an ex vivo mouse model expressing novel fusions provides important information both for sarcoma biology and the appropriate diagnosis of BSTS.

Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression.

SS18-SSX fusion proteins play a central role in synovial sarcoma development, although, the genetic network and mechanisms of synovial sarcomagenesis remain unknown. We established a new ex vivo synovial sarcoma mouse model through retroviral-mediated gene transfer of SS18-SSX1 into mouse embryonic mesenchymal cells followed by subcutaneous transplantation into nude mice. This approach successfully induced subcutaneous tumors in 100% recipients, showing invasive proliferation of short spindle tumor cells with occasional biphasic appearance. Cytokeratin expression was observed in epithelial components in tumors and expression of TLE1 and BCL2 was also shown. Gene expression profiling indicated SWI/SNF pathway modulation by SS18-SSX1 introduction into mesenchymal cells and Tle1 and Atf2 upregulation in tumors. These findings indicate that the model exhibits phenotypes typical of human synovial sarcoma. Retroviral tagging of the tumor identified 15 common retroviral integration sites within the Dnm3 locus as the most frequent in 30 mouse synovial sarcomas. miR-199a2 and miR-214 upregulation within the Dnm3 locus was observed. SS18-SSX1 and miR-214 cointroduction accelerated sarcoma onset, indicating that miR-214 is a cooperative oncomiR in synovial sarcomagenesis. miR-214 functions in a cell non-autonomous manner, promoting cytokine gene expression (e.g., Cxcl15/IL8). Our results emphasize the role of miR-214 in tumor development and disease progression.

Case of mesenchymal tumor with the PPP6R3-USP6 fusion, possible nodular fasciitis with malignant transformation.

Nodular fasciitis (NF) is a self-limiting benign disease that is characterized by rapid proliferation of fibroblastic and myofibroblastic cells. The characteristic gene fusion containing the USP6 gene is a genetic hallmark of NF and MYH9-USP6 is the most frequent fusion, suggesting that NF is not a reactive condition but a neoplastic disease. Malignant transformation of NF has been reported rarely as a single case associated with the PPP6R3-USP6 fusion. Here we report a case of soft part tumor of which the histological feature was a typical NF but showed aggressive and non-regressing growth with local invasion. Targeted RNA sequencing and fluorescence in situ hybridization analysis identified PPP6R3-USP6 with gene amplification. These findings indicate that the present case is the second case of malignant NF, and we suggest potential malignant transformation in certain NF cases.

EWS-FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma.

EWS-FLI1 constitutes an oncogenic transcription factor that plays key roles in Ewing sarcoma development and maintenance. We have recently succeeded in generating an ex vivo mouse model for Ewing sarcoma by introducing EWS-FLI1 into embryonic osteochondrogenic progenitors. The model well recapitulates the biological characteristics, small round cell morphology, and gene expression profiles of human Ewing sarcoma. Here, we clarified the global DNA binding properties of EWS-FLI1 in mouse Ewing sarcoma. GGAA microsatellites were found to serve as binding sites of EWS-FLI1 albeit with less frequency than that in human Ewing sarcoma; moreover, genomic distribution was not conserved between human and mouse. Nevertheless, EWS-FLI1 binding sites within GGAA microsatellites were frequently associated with the histone H3K27Ac enhancer mark, suggesting that EWS-FLI1 could affect global gene expression by binding its target sites. In particular, the Fox transcription factor binding motif was frequently observed within EWS-FLI1 peaks and Foxq1 was identified as the cooperative partner that interacts with the EWS portion of EWS-FLI1. Trib1 and Nrg1 were demonstrated as target genes that are co-regulated by EWS-FLI1 and Foxq1, and are important for cell proliferation and survival of Ewing sarcoma. Collectively, our findings present novel aspects of EWS-FLI1 function as well as the importance of GGAA microsatellites.

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma.

CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). However, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here, we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA. Recipient mice transplanted with eMC-expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small round to short spindle cells. Gene-expression profiles of CDS and eMC revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh, and Zic1 IHC analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro The CDK4/6 inhibitor palbociclib and the soft tissue sarcoma drug trabectedin also blocked the growth of mouse CDS. In summary, our mouse model provides important biological information about CDS and provides a useful platform to explore biomarkers and therapeutic agents for CDS. Cancer Res; 77(11); 2927-37. ©2017 AACR.

Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis.

Alveolar soft part sarcoma (ASPS) is a slowly growing, but highly metastatic, sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and an abundant vascular network that is responsible for metastatic activities at the initial stage. Here, we have generated a new ex vivo mouse model for ASPS that well recapitulates associated angiogenic and metastatic phenotypes. In mouse ASPS, the tumor cells frequently showed tumor intravasation, with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS. High expression of glycoprotein nmb (GPNMB), a transcriptional target of ASPSCR1-TFE3, was observed at the sites of intravasation. ASPS tumor cells also demonstrated enhanced transendothelial migration activity, which was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, a key step in cancer metastasis. The present model also enabled the evaluation of TFE/MITF family transcription factor function, which demonstrated that ASPSCR1-TFEB possessed definitive albeit less marked oncogenic activity than that of ASPSCR1-TFE3. Collectively, our mouse model provides a tool to understand oncogenic, angiogenic, and metastatic mechanisms of ASPS. It also identifies important motifs within the ASPSCR1-TFE3 fusion protein and provides a platform for developing novel therapeutic strategies for this disorder. Cancer Res; 77(4); 897-907. ©2016 AACR.

Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model.

A mouse model that recapitulates the human Ewing's sarcoma-specific chromosomal translocation was generated utilizing the Cre/loxP-mediated recombination technique. A cross between Ewsr1-loxP and Fli1-loxP mice and expression of ubiquitous Cre recombinase induced a specific translocation between Ewsr1 and Fli1 loci in systemic organs of both adult mice and embryos. As a result Ewsr1-Fli1 fusion transcripts were expressed, suggesting a functional Ews-Fli1 protein might be synthesized in vivo. However, by two years of age, none of the Ewsr1-loxP/Fli1-loxP/CAG-Cre (EFCC) mice developed any malignancies, including Ewing-like small round cell sarcoma. Unexpectedly, all the EFCC mice suffered from dilated cardiomyopathy and died of chronic cardiac failure. Genetic recombination between Ewsr1 and Fli1 was confirmed in the myocardial tissue and apoptotic cell death of cardiac myocytes was observed at significantly higher frequency in EFCC mice. Moreover, expression of Ews-Fli1 in the cultured cardiac myocytes induced apoptosis. Collectively, these results indicated that ectopic expression of the Ews-Fli1 oncogene stimulated apoptotic signals, and suggested an important relationship between oncogenic signals and cellular context in the cell-of-origin of Ewing's sarcoma.

Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors.

Ewing's sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing's sarcoma-associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing's sarcoma-like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETS-dependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of ß-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing's sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing's sarcoma and provide clues to the histogenesis of Ewing's sarcoma in bone.

Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia.

Trib1 has been identified as a myeloid oncogene in a murine leukemia model. Here we identified a TRIB1 somatic mutation in a human case of Down syndrome-related acute megakaryocytic leukemia. The mutation was observed at well-conserved arginine 107 residue in the pseudokinase domain. This R107L mutation remained in leukocytes of the remission stage in which GATA1 mutation disappeared, suggesting the TRIB1 mutation is an earlier genetic event in leukemogenesis. The bone marrow transfer experiment showed that acute myeloid leukemia development was accelerated by transducing murine bone marrow cells with the R107L mutant in which enhancement of ERK phosphorylation and C/EBPα degradation by Trib1 expression was even greater than in those expressing wild-type. These results suggest that TRIB1 may be a novel important oncogene for Down syndrome-related acute megakaryocytic leukemia.