Phenotypic heterogeneity in three cases of lymphoid malignancy with chromosomal translocations in 14q11

Lymphoid malignancies bearing translocations involving the region 14q11 are thought to have a T-cell phenotype because their pathogenesis is postulated to involve the aberrant juxtaposition of DNA sequences active in T-cell differentiation (T-cell antigen receptor genes) and proto-oncogenes. We present here three lymphoid malignancies with translocations involving 14q11. Although one had a T-cell phenotype, the other two had B-cell lineage phenotypes. Our findings confirm that not all lymphoid malignancies with translocations involving 14q11 represent T-cell clonal expansions.     

JAK2 Translocations in hematological malignancies: Review of the literature

JAK2 is a cytoplasmic tyrosine kinase whose gene is located on chromosome 9p24. It is involved in the regulation of different cytokines and growth factors and plays an important role in the diagnosis and treatment of myeloproliferative neoplasms (Smith et al., 2008). Translocations involving the JAK2 locus are uncommon with just a few cases described in the literature, and they usually lead to a fusion protein with JAK2 (Patnaik et al., 2010). Chromosome 9p24 abnormalities have been described in myeloid and lymphoid neoplasms including chronic myelogenous leukemia (CML), acute megakaryoblastic leukemia, CD10+ B-cell acute lymphoblastic leukemia, T-cell ALL and chronic myeloproliferative disorders (CMD) (Smith et al., 2008; Lacronique et al., 1997). Although the breakpoints of each translocation are known, characterization of the partner gene has not been done in many of the cases reported due to insufficient sample or other factors. In the present study we review all translocations involving JAK2 that have been reported in the literature.     

Somatic inactivation of Tp53 in hematopoietic stem cells or thymocytes predisposes mice to thymic lymphomas with clonal translocations

TP53 protects cells from transformation by responding to stresses including aneuploidy and DNA double-strand breaks (DSBs). TP53 induces apoptosis of lymphocytes with persistent DSBs at antigen receptor loci and other genomic loci to prevent these lesions from generating oncogenic translocations. Despite this critical function of TP53, germline Tp53^−/− mice succumb to immature T-cell (thymic) lymphomas that exhibit aneuploidy and lack clonal translocations. However, Tp53^−/− mice occasionally develop B lineage lymphomas and Tp53 deletion in pro-B cells causes lymphomas with oncogenic immunoglobulin (Ig) locus translocations. In addition, human lymphoid cancers with somatic TP53 inactivation often harbor oncogenic IG or T-cell receptor (TCR) locus translocations. To determine whether somatic Tp53 inactivation unmasks translocations or alters the frequency of B lineage tumors in mice, we generated and analyzed mice with conditional Tp53 deletion initiating in hematopoietic stem cells (HSCs) or in lineage-committed thymocytes. Median tumor-free survival of each strain was similar to the lifespan of Tp53^−/− mice. Mice with HSC deletion of Tp53 predominantly succumbed to thymic lymphomas with clonal translocations not involving Tcr loci; however, these mice occasionally developed mature B-cell lymphomas that harbored clonal Ig translocations. Deletion of Tp53 in thymocytes caused thymic lymphomas with aneuploidy and/or clonal translocations, including oncogenic Tcr locus translocations. Our data demonstrate that the developmental stage of Tp53 inactivation affects karyotypes of lymphoid malignancies in mice where somatic deletion of Tp53 initiating in thymocytes is sufficient to cause thymic lymphomas with oncogenic translocations.     

A novel role for Greatwall kinase in recovery from DNA damage

Activation of the DNA damage response (DDR) is critical for genomic integrity and tumor suppression. The occurrence of DNA damage quickly evokes the DDR through ATM/ATR-dependent signal transduction, which promotes DNA repair and activates the checkpoint to halt cell cycle progression (Halazonetis et al., 2008; Motoyama and Naka, 2004; Zhou and Elledge, 2000). The "turn off" process of the DDR upon satisfaction of DNA repair, also known as "checkpoint recovery", involves deactivation of DDR elements, but the mechanism is poorly understood. Greatwall kinase (Gwl) has been identified as a key element in the G2/M transition (Archambault et al., 2007; Jackson, 2006; Zhao et al., 2008; Yu et al., 2004; Yu et al., 2006; Zhao et al., 2006) and helps maintain M phase through inhibition of PP2A/B55δ (Burgess et al., 2010; Castilho et al., 2009; Goldberg, 2010; Lorca et al., 2010; Vigneron et al., 2009), the principal phosphatase for Cdk-phosphorylated substrates. Here we show that Gwl also promotes recovery from DNA damage and is itself directly inhibited by the DNA damage response (DDR). In Xenopus egg extracts, immunodepletion of Gwl increased the DDR to damaged DNA, whereas addition of wild type, but not kinase dead Gwl, inhibited the DDR. The removal of damaged DNA from egg extracts leads to recovery from checkpoint arrest and entry into mitosis, a process impaired by Gwl depletion and enhanced by Gwl over-expression. Moreover, activation of Cdk1 after the removal of damaged DNA is regulated by Gwl. Collectively, these results defines Gwl as a new regulator of the DDR, which plays an important role in recovery from DNA     

Quantification of random mutations in the mitochondrial genome

Mitochondrial DNA (mtDNA) mutations contribute to the pathology of a number of age-related disorders, including Parkinson disease [A. Bender et al., Nat. Genet. 38 (2006) 515,Y. Kraytsberg et al., Nat. Genet. 38 (2006) 518], muscle-wasting [J. Wanagat, Z. Cao, P. Pathare, J.M. Aiken, FASEB J. 15 (2001) 322], and the metastatic potential of cancers [K. Ishikawa et al., Science 320 (2008) 661]. The impact of mitochondrial DNA mutations on a wide variety of human diseases has made it increasingly important to understand the mechanisms that drive mitochondrial mutagenesis. In order to provide new insight into the etiology and natural history of mtDNA mutations, we have developed an assay that can detect mitochondrial mutations in a variety of tissues and experimental settings [M. Vermulst et al., Nat. Genet. 40 (2008) 4, M. Vermulst et al., Nat. Genet. 39 (2007) 540]. This methodology, termed the Random Mutation Capture assay, relies on single-molecule amplification to detect rare mutations among millions of wild-type bases [J.H. Bielas, L.A. Loeb, Nat. Methods 2 (2005) 285], and can be used to analyze mitochondrial mutagenesis to a single base pair level in mammals.     

Potential G-quadruplex formation at breakpoint regions of chromosomal translocations in cancer may explain their fragility

Genetic alterations like point mutations, insertions, deletions, inversions and translocations are frequently found in cancers. Chromosomal translocations are one of the most common genomic aberrations associated with nearly all types of cancers especially leukemia and lymphoma. Recent studies have shown the role of non-B DNA structures in generation of translocations. In the present study, using various bioinformatic tools, we show the propensity of formation of different types of altered DNA structures near translocation breakpoint regions. In particular, we find close association between occurrence of G-quadruplex forming motifs and fragile regions in almost 70% of genes involved in rearrangements in lymphoid cancers. However, such an analysis did not provide any evidence for the occurrence of G-quadruplexes at the close vicinity of translocation breakpoint regions in nonlymphoid cancers. Overall, this study will help in the identification of novel non-B DNA targets that may be responsible for generation of chromosomal translocations in cancer.     

Centromere Epigenetics in Plants

The centromere is an essential chromosome site at which the kinetochore forms and loads proteins needed for faithful segregation during the cell cycle and meiosis(Houben et al., 1999;Cleveland et al.,2003;Ma et al.,2007;Birchler and Han,2009).Centromere specific sequences such as tandem repeats or transposable elements evolve quickly both within and between the species but have conserved kinetochore proteins(Henikoff and Furuyama,2010).The universal feature     

H3K27 demethylases, at long last

Methylation of lysine 27 on histone H3 (H3K27me) by the Polycomb complex (PRC2) proteins is associated with gene silencing in many developmental processes. A cluster of recent papers (Agger et al., 2007; De Santa et al., 2007; Lan et al., 2007; Lee et al., 2007) identify the JmjC-domain proteins UTX and JMJD3 as H3K27-specific demethylases that remove this methyl mark, enabling the activation of genes involved in animal body patterning and the inflammatory response.     

Mighty Piwis defend the germline against genome intruders

Piwis are a germline-specific subclass of the Argonaute family of RNA interference (RNAi) effector proteins that are associated with a recently discovered group of small RNAs (piRNAs). Recent studies in Drosophila and zebrafish directly implicate Piwi proteins in piRNA biogenesis to maintain transposon silencing in the germline genome (Brennecke et al., 2007; Gunawardane et al., 2007; Houwing et al., 2007). This function may be conserved in mice as loss of Miwi2, a mouse Piwi homolog, leads to germline stem cell and meiotic defects correlated with increased transposon activity (Carmell et al., 2007).     

After hours keeps clock researchers CRYing Overtime

Three recent reports, including one in this issue of Cell, reveal that the circadian regulator CRY is targeted for degradation by the F box E3 ubiquitin ligase FBXL3 (Siepka et al., 2007; Busino et al., 2007; Godinho et al., 2007). These studies confirm the importance of targeted protein degradation as a key design feature of the mammalian circadian clock.     

Dscam and neuronal uniqueness

In the fruit fly Drosophila the gene encoding the cell adhesion molecule Dscam generates alternatively spliced mRNAs that can be translated into thousands of different protein isoforms. Three recent papers show that isoform-specific homophilic Dscam interactions cause dendritic branches of the same neuron to avoid each other (Hughes et al., 2007; Soba et al., 2007; Matthews et al., 2007). This process ensures the correct patterning of dendrites in the peripheral nervous system.     

Interrelation of the dynamics of antigen intake into bone marrow and the proliferation of hematopoietic stem cells

As it is previously shown (Tsyrlova et al., 1986), the level of humoral immune response is not only determined by the reaction of peripheral lymphoid system on antigenic effect, but also is bound up with the observed stem blood cell (SBC) proliferation in bone marrow (Frindel et al., 1976, Kozlov et al., 1982). Dynamics of label accumulation in bone marrow was examined when injecting antigen--sheep red blood cells labeled by radioisotope 51Cr, 125I. The peak of label accumulation in bone marrow, accompanied by the increase in proliferative SBC, was observed on the 3rd day after antigen injection. Furthermore in the course of immunization 51Cr labeled macrophage assortment was changed in time in such a way that a greater number of macrophages was accumulated in bone marrow on the 3rd and 4th days in the immunized animals in comparison with the intact ones. The macrophages in bone marrow are likely to take part in antigen uptake and to mediate its effect on SBC proliferation.     

Effects of chromatin decondensation on alternative NHEJ

In cells of higher eukaryotes, repair of DNA double strand breaks (DSBs) utilizes different forms of potentially error-prone non-homologous end joining (NHEJ): canonical DNA-PK-dependent (C-NHEJ) and alternative backup pathways (A-NHEJ). In contrast to C-NHEJ, A-NHEJ shows pronounced efficiency fluctuations throughout the cell cycle and is severely compromised as cells cease proliferating and enter the plateau phase (Windhofer et al., 2007 [23]). The molecular mechanisms underpinning this response remain unknown but changes in chromatin structure are prime candidate-A-NHEJ-modulators. Since parameters beyond chromatin acetylation appear to determine A-NHEJ efficiency (Manova et al., 2012 0210 and 0380), we study here the role of chromatin decondensation mediated either by treatment with 5′-aza-2′-deoxycytidine (AzadC) or growth in hypotonic conditions, on A-NHEJ. We report that both treatments have no detectable effect on C-NHEJ but provoke, specifically for A-NHEJ, cell-growth-dependent effects. These results uncover for the first time a link between A-NHEJ and chromatin organization and provide means for understanding the regulatory mechanisms underpinning the growth-state dependency of A-NHEJ. A-NHEJ is implicated in the formation of chromosomal translocations and in chromosome fusions that underlie genomic instability and carcinogenesis. The observations reported here may therefore contribute to the development of drug-based A-NHEJ suppression-strategies aiming at optimizing cancer treatment outcomes and possibly also at suppressing carcinogenesis.     

Bone remodeling, energy metabolism, and the molecular clock

The adult skeleton is constantly renewed through bone remodeling. Four recent papers (Baldock et al., 2007; Lee et al., 2007; Lundberg et al., 2007; Sato et al., 2007) provide new insights into central and peripheral control of this remodeling sequence. Two of the studies add to our knowledge of the complex hypothalamic modulation of bone turnover mediated by NMU and NPY via the sympathetic nervous system, while the other two focus on the peripheral neural target, the osteoblast, and its regulation by neuropeptides and osteocalcin. These findings support a new paradigm concerning the regulation of bone remodeling and provide a foundation for novel approaches to preventing osteoporosis.     

44 Circular dichroism (CD) studies of the interaction between G-quadrulexes/I-motif with saffron secondary active metabolites

Telomeric DNA contains some unique secondary structures, such as G-quadruplex and I-motif. These structures may be stabilized or changed by binding to specific proteins or small molecules. In continuation of our previous studies on the interaction between crocin and crocetin, as the natural C20 carotenoids, and picrocrocin and safranal, as the natural monoterpene aldehydes, obtained from saffron and DNA (Bathaie et al., 2007; Hoshyar et al., 2008), herein, we report the in vitro effect of these saffron metabolites on the mentioned structures (Hoshyar et al., 2012). Circular dichroism (CD) data indicate that crocetin has higher affinity for these structures. Safranal and crocin induce little change in the I-motif and G-quadruplex, respectively. The molecular docking confirms the experimental data and indicates the minor groove binding of ligands with G-quadruplex. Effects of these ligands on the stability of these structures is studied using some other techniques and determination of thermodynamic parameters.     

Epigenetic Variations in Plant Hybrids and Their Potential Roles in Heterosis

Heterosis,one of the most important biological phenomena,refers to the phenotypic superiority of a hybrid over its genetically diverse parents with respect to many traits such as biomass,growth rate and yield.Despite its successful application in breeding and agronomic production of many crop and animal varieties,the molecular basis of heterosis remains elusive.The classic genetic explanations for heterosis centered on three hypotheses:dominance (Davenport,1908;Bruce,1910;Keeble and Pellew,1910;Jones,1917),overdominance (East,1908;Shull,1908) and epistasis (Powers,1944;Yu et al.,1997).However,these hypotheses are largely conceptual and not connected to molecular principles,and are therefore insufficient to explain the molecular basis of heterosis (Birchler et al.,2003).Recently,many studies have explored the molecular mechanism of heterosis in plants at a genome-wide level.These studies suggest that global differential gene expression between hybrids and parental lines potentially contributes to heterosis in plants (e.g.,Swanson-Wagner et al.,2006;Zhang et al.,2008;Wei et al.,2009;Song et al.,2010).Research suggests that genetic components,including cis-acting elements and trans-acting factors,are critical regulators of differential gene expression in hybrids (Hochholdinger and Hoecker,2007;Springer and Stupar,2007;Zhang et al.,2008).However,other research indicates that epigenetic components,the regulators of chromatin states and genome activity,also have the potential to impact heterosis (e.g.,Ha et al.,2009;He et al.,2010;Groszmann et al.,2011;Barber et al.,2012;Chodavarapu et al.,2012;Greaves et al.,2012a;Shen et al.,2012).     

Mechanisms involved in the neurotoxic and cognitive effects of developmental methamphetamine exposure

Methamphetamine exposure in utero leads to a variety of higher‐order cognitive deficits, such as decreased attention and working, and spatial memory impairments in exposed children (Piper et al., 2011; Roussotte et al., 2011; Kiblawi et al., 2011). As with other teratogens, the timing of methamphetamine exposure greatly determines its effects on both neuroanatomical and behavioral outcomes. Methamphetamine exposure in rodents during the third trimester human equivalent period of brain development results in distinct and long‐lasting route‐based and spatial navigation deficits (Williams et al., 2003; Vorhees et al., 2005, 2008, 2009;). Here, we examine the impact of neonatal methamphetamine‐induced neurotoxicity on behavioral outcomes, neurotransmission, receptor changes, plasticity proteins, and DNA damage. Birth Defects Research (Part C) 108:131–141, 2016. © 2016 Wiley Periodicals, Inc.     

Discussion on the metabolism of c-myc mRNA and protein

The c-myc gene is expressed in a variety of actively growing cells and tissues including lymphoblastoid cell lines made in vitro by EBV infection (Hamlyn & Rabbitts 1983). The gene is implicated in the derivation of Burkitt's lymphoma because of its association with consistent chromosomal translocations (Dalla-Favera et al. 1982; Neel et al. 1982; Taub et al. 1982) and in, for example, some colon carcinomas where the gene is amplified (Alitalo et al. 1983). To understand the formation of these cancers, we must determine the function of the c-myc protein in the cell. In this discussion we describe some features of c-myc metabolism which indicate that its expression may normally be strictly modulated; it is possible that the potential oncogenic effect of c-myc in various tumours is the result of loss of this ability to modulate its activity.     

Smac mimetics and TNFalpha: a dangerous liaison?

Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. It has been thought that small-molecule mimetics of Smac, an endogenous IAP antagonist, might potentiate apoptosis in cancer cells by promoting caspase activation. However, three recent papers, two in Cell (Vince et al., 2007; Varfolomeev et al., 2007) and one in Cancer Cell (Petersen et al., 2007), now report that Smac mimetics primarily kill cancer cells via a different mechanism, the induction of autoubiquitination and degradation of cIAPs, which culminates in TNFalpha-mediated cell death.