The AML1-CBF␤ transcription factor complex is essential for the definitive hematopoiesis of all lineages and is the most frequent target of chromosomal rearrangements in human leukemia. In the t(8;21) translocation associated with acute myeloid leukemia (AML), the AML1(CBFA2/PEBP2␣B) gene is juxtaposed to the MTG8(ETO/CDR) gene. We show here that the resultant AML1-MTG8 gene product specifically and strongly interacts with an 85-kDa phosphoprotein. Molecular cloning of cDNA indicated that the AML1-MTG8-binding protein (MTGR1) is highly related to MTG8 and similar to Drosophila Nervy. Comparison of amino acid sequences among MTGR1, MTG8, and Nervy revealed four evolutionarily conserved regions (NHR1 to NHR4). Ectopic expression of AML1-MTG8 in L-G murine myeloid progenitor cells inhibits differentiation to mature neutrophils and induces cell proliferation in response to granulocyte colony-stimulating factor (G-CSF). Analysis with C-terminal deletion mutants of AML1-MTG8 indicated that the region of 51 residues (488 to 538), which contains NHR2, is essential for the induction of G-CSF-dependent cell proliferation. Immunoprecipitation analysis indicates that this region is required for AML1-MTG8 to form a stable complex with MTGR1. Overexpression of MTGR1 stimulates AML1-MTG8 to induce G-CSF-dependent proliferation of L-G cells and to interfere with AML1-dependent transcription. These results suggest that AML1-MTG8 could function as a complex with MTGR1 and that the complex might be important in promoting leukemogenesis.Chromosome translocations associated with human leukemia frequently involve genes that code for a variety of transcriptional factors implicated in the regulation of normal hematopoiesis (44). The AML1-CBF␤ transcription factor complex is the most frequent target of these translocations. The AML1 gene (on chromosome 21) was identified through its involvement in t(8;21) translocation, which occurs in ϳ40% of cases of acute myeloid leukemia with the M2 French-American-British subtype (28). In this translocation, the AML1 gene is juxtaposed to the gene which encodes a zinc finger-containing protein MTG8 (also known as ETO and CDR), resulting in the expression of the AML1-MTG8 chimeric protein (4,19,29,32). In addition, the AML1 gene is fused with the TEL gene, which encodes a member of the Ets family of transcription factors, to form a TEL-AML1 chimeric product by t(12;21) translocation. The resultant chimeric transcripts are detected in pediatric B-cell progenitor acute lymphoblastic leukemia, the most common leukemia seen in children (10, 46). Furthermore, AML1-containing fusion products are formed by t(3;21) translocation, which occurs in myelodysplastic syndrome and the blast crisis phase of chronic myelogenous leukemia (27,35,36). Moreover, CBF␤, which forms a heterodimer with AML1, is also the target of leukemia-associated chromosomal rearrangement and makes a fusion protein with smooth muscle myosin heavy chain (MYH11) in inv(16), which is often observed in AML-M4Eo (22).The AML1 family of transc...

JPLT-2 protocol achieved satisfactory survival among children with non-metastatic hepatoblastoma. New approaches are needed for patients with metastatic diseases.

Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their “cell of origin” derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.

p300, which was originally cloned as a nuclear binding target of the adenovirus E1A oncoprotein, forms a family with cyclic-AMP response element binding protein (CREB)-binding protein (CBP). p300/CBP are considered to be transcriptional coactivators that connect the basal transcriptional machinery to various DNA-binding transcriptional factors. p300/CBP are implicated in both cell differentiation and regulation of cell-cycle. We identify here that the p300 gene is fused to the MLL gene and that in-frame MLL-p300 fusion protein is generated in acute myeloid leukemia (AML) with t(11; 22)(q23; q13). These findings suggest that the basis for the leukemogenesis of t(11; 22)-AML is the inability of p300 to regulate cell-cycle and cell differentiation after fusion with MLL.