Carlo M. Croce

Bio: Carlo M. Croce is an academic researcher from Ohio State University. The author has contributed to research in topics: microRNA & Cancer. The author has an hindex of 198, co-authored 1135 publications receiving 189007 citations. Previous affiliations of Carlo M. Croce include University of Nebraska Medical Center & University of California, Los Angeles.

Crystal structure of MTCP-1: Implications for role of TCL-1 and MTCP-1 in T cell malignancies

Abstract: Chromosomal rearrangements in the T cell malignancies observed in T cell prolymphocytic leukemias, and in patients with Ataxia telangiectasia involve the translocation of one T cell receptor gene to either chromosome 14q32 or Xq28 (1–3). These genetic aberrations juxtapose cellular protooncogenes to enhancer elements leading to deregulation of oncogene expression (4). The two oncogenes involved in these translocations are MTCP-1 and TCL-1, which constitute a family of genes involved in lymphoid proliferation and T cell malignancies (2, 5, 6). The MTCP-1 (mature T cell proliferation-1) gene in the human X chromosome was the first candidate gene involved in the leukemogenesis of mature T cells (7). Aberrant or overexpressed MTCP-1 transcripts are found in the rare, but recurrent, chromosomal translocation t(X;14) in T cell proliferative diseases (8). About 10% of patients with the genetic disease Ataxia telangiectasia have clonal T cell proliferations with this cytogenetic aberration (1–3). MTCP-1 has two short ORFs that express A1 and B1 transcripts. The shorter A1 transcript is widely expressed in both tumor and nontumor cells. Expression of the B1 transcript is restricted to mature T cell proliferations with t(X;14) translocations (9), including T cell prolymphocytic leukemia tumors from patients with ataxia telangiectasia (10). The function of the B1 transcript of MTCP-1 is not known, but it encodes for a protein of 107 amino acids. The TCL-1 oncogene maps at chromosome 14q32.1 (5). Chromosomal rearrangements at the TCL-1 locus are associated with T cell leukemia of the mature phenotype such as T cell prolymphocytic leukemia, adult T cell leukemia, and chronic T cell leukemias in patients with immunodeficiency syndrome Ataxia telangiectasia. TCL-1 is activated in T cell leukemias and lymphomas by chromosome translocations or inversions that juxtapose the α/δ or the β locus of the T cell receptor to the TCL-1 oncogene. TCL-1 is expressed at high levels in pre-B cells and immature thymocytes, but not in mature B or T cells (11). No expression of TCL-1 was observed in cell lines derived from normal human tissues. Ataxia telangiectasia patients with chromosome 14 rearrangements show expression of TCL-1 in leukemic T cells (10, 12). Similarly, the murine homolog of TCL-1 is expressed early in embryonic development in immature T and B cells (13). The TCL-1 gene codes for a protein of 114 amino acid residues and molecular weight of 14,000 daltons (6). TCL-1 and MTCP-1 proteins share 40% identical amino acid residues and 61% similar amino acids, which strongly suggested that their tertiary structures are similar. However, no similarity was found with other human genes. Therefore, TCL-1 and MTCP-1 represent members of a unique family of genes involved in lymphoid proliferation and T cell malignancies. Human recombinant TCL-1 and MTCP-1 proteins have been expressed in Escherichia coli and purified for structural analysis to investigate their role in development of T cell malignancies (14). CD spectra at neutral pH are similar for both proteins and suggest β-sheet secondary structure. The crystal structure of MTCP-1 has been determined and refined to an R factor of 0.21 at 2.0 Å resolution. A model has been built of the structure of TCL-1. Analysis of these structures and the implications for the cellular function of these oncogene products are discussed.

Xenogeneic gene expression in chimeric mice derived from rat--mouse hybrid cells.

Abstract: Thymidine kinase-deficient OTT6050 mouse teratocarcinoma cells were fused with hypoxanthine phosphoribosyltransferase-deficient Fu5AH rat hepatoma cells by means of inactivated Sendai virus. The resulting hybrid cells, which were selected in hypoxanthine/aminopterin/thymidine medium, retained almost all of the mouse chromosomes and various numbers of rat chromosomes, and showed many chromosomal rearrangements. The hybrid cells, as well as both parental lines, formed tumors after subcutaneous injection into athymic nude mice. Single rat--mouse hybrid cells from a clonally established subline were transplanted into C57BL6/J mouse blastocysts carrying many genetic markers suitable for the detection of hybrid cell-derived tissue contributions. From 144 blastocysts, each of which was injected with a hybrid cell and then surgically transferred to the uterus of a pseudopregnant foster mother, 62 adult mice developed without any visible coat mosaicism. However, three of these mice showed internal hybrid-cell participation in their livers and a limited number of organs of endomesodermal origin. A tumor classifiable as hemangio endothelioma was found in the liver, the only mosaic tissue, of one of the chimeric mice. Nine different rat-specific enzyme variants were detected in the mosaic organs. A considerable number of variations concerning the presence and quantitative activity of the foreign gene products probably resulted from chromosomal segregation, tissue-specific gene activity, or dosage compensation during differentiation in vivo. Our results demonstrate that cultured malignant rat--mouse hybrid cells differentiate normally and become functionally integrated during development. The appearacne in vivo of certain rat-specific gene products that are not found in the hybrid cells under conditions in vitro indicates differential gene expression of the introduced xenogeneic chromosomes.

Molecular Genetics of 11q23 Chromosome Translocations

Abstract: Publisher Summary This chapter focuses on the modular genetics of 11q23 chromosome translocations. The new cancer genes identified through this approach—particularly in the leukemias and lymphomas— have proved to be oncogenic only in a specific cell lineage and, in some cases, only at a particular stage of differentiation. A remarkable exception is a gene recently identified at chromosome band 11q23 that appears to be involved in a spectrum of hematopoietic tumors with a variety of phenotypes. As cytogenetic techniques have improved and been corroborated by other methods, no fewer than 20 different 11q23 translocations have now been identified in various childhood and adult acute leukemias. The association of band 11q23 with a variety of chromosome translocations prompted attempts to examine genes mapped to the breakpoint cluster region for their location regarding the breakpoints and for possible rearrangements.

Southern Blot Analysis of ALL-1 Rearrangements at Chromosome 11q23 in Acute Leukemia

Abstract: The chromosome 11q23 band is a genetic region frequently involved in nonrandom karyotypic abnormalities of acute leukemia. A genomic locus named ALL-1 or MLL, where 11q23 breakpoints are clustered, has been recently cloned and characterized. We have made use of an ALL-1-specific probe in Southern blot experiments to analyze the configuration of this gene in a large series of acute leukemia patients, representative of all different myeloid and lymphoid subtypes. Nine of 145 cases (6.2%) showed abnormal ALL-1 restriction fragments in leukemic DNAs. Of these nine cases, five patients in whom karyotypic data were available displayed chromosome 11q23 aberrations, including t(4;11) (three cases) and t(9;11) (two cases). Immunophenotypic and morphocytochemical characterization of ALL-1-rearranged acute leukemia revealed prevalence of poorly differentiated B lymphoid and/or monoblastic features. Considering the whole series, ALL-1 rearrangements were significantly associated with female sex, higher white blood cell counts at presentation, and very poor clinical outcome. The presence of residual disease was molecularly documented in one case at the time of clinical remission after induction treatment and was followed by early relapse. We conclude that ALL-1 rearrangements are new molecular markers of human leukemia with considerable diagnostic and prognostic relevance.

Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

Abstract: The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSIBLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.

Analyzing real-time PCR data by the comparative C(T) method.

Abstract: Two different methods of presenting quantitative gene expression exist: absolute and relative quantification. Absolute quantification calculates the copy number of the gene usually by relating the PCR signal to a standard curve. Relative gene expression presents the data of the gene of interest relative to some calibrator or internal control gene. A widely used method to present relative gene expression is the comparative C(T) method also referred to as the 2 (-DeltaDeltaC(T)) method. This protocol provides an overview of the comparative C(T) method for quantitative gene expression studies. Also presented here are various examples to present quantitative gene expression data using this method.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。