Anomalous lattice expansion of RuSr2Eu1.5Ce0.5Cu2O10(Ru-1222) magneto superconductor: A low temperature X-ray diffraction study

This is the first report of the observation of the onset of excess volume and also of the strain along the a-axis near the magnetic ordering temperature in Ru-1222 superconductor, and indicates a coupling between the lattice and the magnetism in this system. Magnetization, magneto transport and thermoelectric power measurements being carried out on the same sample are also reported.Comment: 15 Pages Text Plus Figs. Physica C (2006) accepte

Role of Carbon in Enhancing the Performance of MgB2 superconductor

The enhancement of the critical current density (Jc(H)) of carbon and nano-SiC doped MgB2 is presented and compared. The upper critical field (Hc2) being determined from resistivity under magnetic field experiments is though improved for both C substitution and nano-SiC addition the same is more pronounced for the former. In MgB2-xCx carbon is substituted for boron that induces disorder in the boron network and acts as internal pinning centres. The optimal Jc(H) values are obtained for x = 0.1 sample . In case of nano-SiC doped in MgB2, the Jc(H) improves more profoundly and two simultaneous mechanisms seems responsible to this enhancement. Highly reactive nano-SiC releases free carbon atom, which gets easily incorporated into the MgB2 lattice to act as intrinsic pinning centres. Further enhancement is observed for higher nano-SiC concentrations, where the un-reacted components serve as additional extrinsic pinning centres.Comment: 17 Pages text + Fig

Ectopic expression of the homeobox gene Cdx2 is the key transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia; a novel mechanism in AML.

This thesis demonstrates for the first time that activation of a proto-oncogene by a chromosomal translocation can be the key step in myeloid leukemogenesis, even if a fusion gene is generated and expressed in parallel. This mechanism of AML leukemogenesis was proven in a murine model of t(12;13)(p13;q12) AML, showing that myeloid leukemogenesis is induced by the ectopic expression of Cdx2 and not by the ETV6/CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. In contrast, mice which were transplanted with BM cells expressing the fusion gene alone did not develop AML. The transforming activity of Cdx2 was dependent on an intact homeodomain and the N-terminal transactivation domain. Although mice transplanted with ETV6/CDX2 expressing BM cells did not develop overt disease, these animals suffered from a mild myeloproliferation. Experiments testing the effect of simultaneous expression of the Cdx2 and the fusion gene showed no acceleration or change in phenotype of the disease compared to expression of Cdx2 alone, again demonstrating that the ectopic expression of Cdx2 was the key event in this leukemia model. These findings link proto-oncogene activation to myeloid leukemogenesis, an oncogenic mechanism so far associated mainly with lymphoid leukemias and lymphomas. Our model constitutes the first functional proof that activation of a proto-oncogene by a chromosomal translocation is the key leukemogenic event in AML. As many fusion proteins expressed in AML have clearly no leukemogenic potential in experimental in vivo models, this mechanism might be more important for the development of AML than previously thought and should be included in the pathogenetic models of this disease

The AML1-ETO fusion gene and the FLT3 lenght mutation collaborate in inducing acute leukemia in mice.

The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO-positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO-positive leukemias

The homeobox gene CDX2 is aberrantly expressed and associated with an inferior prognosis in patients with acute lymphoblastic leukemia.

Molecular characterization of acute lymphoblastic leukemia (ALL) has greatly improved the ability to categorize and prognostify patients with this disease. In this study, we show that the proto-oncogene CDX2 is aberrantly expressed in the majority of cases with B-lineage ALL and T-ALL. High expression of CDX2 correlated significantly with the ALL subtype pro-B ALL, cALL, Ph+ ALL and early T-ALL. Furthermore, high expression of CDX2 was associated with inferior overall survival and showed up as a novel and strong risk factor for ALL in bivariate analysis. Functional analyses showed that overexpression of Cdx2 in murine bone marrow progenitors perturbed genes involved in lymphoid development and that depletion of CDX2 in the human ALL cell line Nalm6 inhibited colony formation. These data indicate that aberrant CDX2 expression occurs frequently and has prognostic impact in adult patients with ALL

MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML

Contains fulltext : 159977.pdf (publisher's version ) (Open Access

The leukemogenicity of Hoxa9 depends on alternative splicing.

Although the transforming potential of Hox genes is known for a long time, it is not precisely understood to which extent splicing is important for the leukemogenicity of this gene family. To test this for Hoxa9, we compared the leukemogenic potential of the wild-type Hoxa9, which undergoes natural splicing, with a full-length Hoxa9 construct, which was engineered to prevent natural splicing (Hoxa9FLim). Inability to undergo splicing significantly reduced in vivo leukemogenicity compared to Hoxa9-wild-typed. Importantly, Hoxa9FLim could compensate for the reduced oncogenicity by collaborating with the natural splice variant Hoxa9T, as co-expression of Hoxa9T and Hoxa9FLim induced AML after a comparable latency time as wild-type Hoxa9. Hoxa9T on its own induced AML after a similar latency as Hoxa9FLim, despite its inability to bind DNA. These data assign splicing a central task in Hox gene mediated leukemogenesis and suggest an important role of homeodomain-less splice variants in hematological neoplasms

Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia.

The mechanisms underlying deregulation of HOX gene expression in AML are poorly understood. The ParaHox gene CDX2 was shown to act as positive upstream regulator of several HOX genes. In this study, constitutive expression of Cdx2 caused perturbation of leukemogenic Hox genes such as Hoxa10 and Hoxb8 in murine hematopoietic progenitors. Deletion of the N-terminal domain of Cdx2 abrogated its ability to perturb Hox gene expression and to cause acute myeloid leukemia (AML) in mice. In contrast inactivation of the putative Pbx interacting site of Cdx2 did not change the leukemogenic potential of the gene. In an analysis of 115 patients with AML, expression levels of CDX2 were closely correlated with deregulated HOX gene expression. Patients with normal karyotype showed a 14-fold higher expression of CDX2 and deregulated HOX gene expression compared with patients with chromosomal translocations such as t(8:21) or t(15;17). All patients with AML with normal karyotype tested were negative for CDX1 and CDX4 expression. These data link the leukemogenic potential of Cdx2 to its ability to dysregulate Hox genes. They furthermore correlate the level of CDX2 expression with HOX gene expression in human AML and support a potential role of CDX2 in the development of human AML with aberrant Hox gene expression

Aml1-eto collaborates with the homeobox genes meis1 and meis2 in inducing aml

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