t(5;9)(q33;q22)

Review on t(5;9)(q33;q22), with data on clinics, and the genes involved

ITK (IL2-inducible T-cell kinase)

Review on ITK (IL2-inducible T-cell kinase), with data on DNA, on the protein encoded, and where the gene is implicated

Marginal zone lymphomas in children and the young adult population; characterization of genetic aberrations by FISH and RT-PCR

Marginal zone lymphomas present rarely in children and young adults as either primary nodal or extranodal disease and have an excellent prognosis. To date, chromosomal aberrations have not been analyzed in the pediatric and young adult population. We undertook a study to analyze genetic alterations in nodal and extranodal marginal zone lymphomas in children and young adults using fluorescence in situ hybridization (FISH) and RT-PCR. These findings were correlated with clinical features at presentation and immunophenotype. Forty-one cases were identified meeting these criteria. The age range was 1.5-29 years old with 49% of the cases <18 years of age. 73% of the marginal zone lymphoma cases showed evidence of light chain restriction by immunohistochemistry or flow cytometry. CD43 was coexpressed in 83%. 85% of the marginal zone lymphoma cases tested showed evidence of immunoglobulin heavy chain gene rearrangement. Fifty-nine percent of the cases were nodal marginal zone lymphomas with a median age at presentation of 16 years and an M/F ratio of 7:1. Twenty-one percent of the nodal marginal zone lymphoma cases contained genetic aberrations. Seventeen percent contained trisomy 18 with one case containing an additional trisomy 3. A translocation of the immunoglobulin heavy chain gene to an unknown partner gene was present in one case. Forty-one percent of the cases were extranodal marginal zone lymphomas with a median age of 24 years and a M/F ratio of 1.4:1. Eighteen percent of the extranodal marginal zone lymphoma cases contained genetic aberrations. The t(14;18) involving the IGH and MALT1 genes was present in one case, tetraploidy was present in one case, and another case contained trisomy 3. Overall the incidence of genetic aberrations in marginal zone lymphomas in the pediatric and young adult population is low, but the aberrations seen are similar to those seen in the adult population

Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although mechanisms of BCR/ABL1-induced transformation are well-defined, little is known about effector-molecules contributing to malignant expansion and the extramedullary spread of leukemic SC (LSC) in CML. We have identified the cytokine-targeting surface enzyme dipeptidylpeptidase-IV (DPPIV/CD26) as a novel, specific and pathogenetically relevant biomarker of CD34+/CD38─ CML LSC. In functional assays, CD26 was identified as target enzyme disrupting the SDF-1-CXCR4-axis by cleaving SDF-1, a chemotaxin recruiting CXCR4+ SC. CD26 was not detected on normal SC or LSC in other hematopoietic malignancies. Correspondingly, CD26+ LSC decreased to low or undetectable levels during successful treatment with imatinib. CD26+ CML LSC engrafted NOD-SCID-IL-2Rγ−/− (NSG) mice with BCR/ABL1+ cells, whereas CD26─ SC from the same patients produced multilineage BCR/ABL1– engraftment. Finally, targeting of CD26 by gliptins suppressed the expansion of BCR/ABL1+ cells. Together, CD26 is a new biomarker and target of CML LSC. CD26 expression may explain the abnormal extramedullary spread of CML LSC, and inhibition of CD26 may revert abnormal LSC function and support curative treatment approaches in this malignancy

Enhanced expression of the stemness-related factors OCT4, SOX15 and TWIST1 in ectopic endometrium of endometriosis patients

Abstract Background Current evidence suggests that endometrial-derived stem cells, spilled in the peritoneal cavity via retrograde menstruation, are key players in the establishment of endometriotic lesions. The aim of this study was to determine the presence and distribution of the stemness-related factors OCT4, SOX15, TWIST1 and DCAMLK1 in women with and without endometriosis. Methods Immunohistochemical analysis was used to determine stromal and epithelial expression of OCT4, SOX15, TWIST1 and DCAMLK1 in endometriosis patient (EP) endometrium (n = 69) and endometriotic tissue (n = 90) and in control endometrium (n = 50). Quantitative Real-Time PCR of OCT4, SOX15 TWIST1 and DCAMLK1 was performed in paired samples of EP endometrium and endometriotic tissue. Co-immunofluorescence staining was performed for OCT4 and SOX15. For statistical analyses we used unpaired t-test, Fisher combination test and Spearman test. For paired analyses, paired t-test and McNemar test were used. Results We detected a significant correlation between the expression of the established stem cell marker OCT4 and the stemness-related markers SOX15 (p < 0.001) and TWIST1 (p = 0.002) but not DCAMLK1. We showed a colocalization of SOX15 and OCT4 in epithelial and stromal cells of endometriotic tissue by coimmunofluorescence. A concordant expression of OCT4 and SOX15 in the same sample was observed in epithelial cells of the endometriotic tissue (71.7%). The expression of stemness-related factors was not associated with proliferative or secretory phase of the menstrual cycle in endometriosis patients but was found to be differentially expressed during the menstrual cycle in the control group. Increased expression of epithelial OCT4, SOX15 and TWIST1 was detected in endometriotic tissue compared to EP endometrium in paired (p = 0.021, p < 0.001 and p < 0.001) and unpaired analysis (p = 0.040, p < 0.001 and p = 0.001). Conclusion Our findings support the hypothesis that upregulation of stem cell-related factors contribute to the establishment of endometriotic lesions. Trial registration The study was approved by the institutional review board (545/2010 on 6th of May 2014) of the Medical University of Vienna ( http://ethikkommission.meduniwien.ac.at/fileadmin/ethik/media/dokumente/register/alle_2010.pdf )

The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma

Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T cell kinase (ITK)–spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)–proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL

Materials in particulate form for tissue engineering. 1 Basic concepts

For biomedical applications, materials small in size are growing in importance. In an era where ‘nano’ is the new trend, micro- and nano-materials are in the forefront of developments. Materials in the particulate form aim to designate systems with a reduced size, such as micro- and nanoparticles. These systems can be produced starting from a diversity of materials, of which polymers are the most used. Similarly, a multitude of methods are used to produce particulate systems, and both materials and methods are critically reviewed here. Among the varied applications that materials in the particulate form can have, drug delivery systems are probably the most prominent, as these have been in the forefront of interest for biomedical applications. The basic concepts pertaining to drug delivery are summarized, and the role of polymers as drug delivery systems conclude this review