Targeting translation in acute myeloid leukemia: A new paradigm for therapy?

The mammalian Target Of Rapamycin Complex 1 (mTORC1) pathway is commonly activated in cancer cells including acute myeloid leukemia (AML) and has been designed as a major target for cancer therapy. However, the efficacy of rapalogs (mTORC1 inhibitors) is limited in AML, due to the feedback activation of PI3K or ERK signaling pathways upon mTORC1 inhibition, which pathways should be simultaneously targeted to enhance the anti-leukemic activity of rapalogs. Moreover, the mRNA translation process is mTORC1-independent in AML, although markedly contributing to oncogenesis in this disease, and this also strongly participates to rapalogs resistance. Translation inhibition could be achieved by directly targeting the translation initiating complex using the 4EGI-1 compound, anti-eIF4E antisense oligonucleotides or the antiviral drug ribavirin or by second generation mTOR inhibitors (TORkinhibs). These new approaches represent promising perspectives for AML therapy that should have clinical development in the future.     

Low-dose Ara-C in the treatment of acute leukemia. Cytotoxicity or differentiation induction?

The differentiation inducing effect of low-dose Ara-C on human myeloid leukemic cells was studied in two patients with subacute myelocytic and subacute myelomonocytic leukemia in vivo and in vitro. By continuous i.v. administration of 10 mg Ara-C/m2 over 12 h daily for 12 or 20 days complete remissions were obtained in both patients with normalization of the incidence of the committed progenitor cells BFU-E and CFU-C in the marrow while the incidence of pluripotent CFU-GEMM remained subnormal. Parallel cultures of the patients' bone marrow cells in diffusion chambers (DC) implanted in mice demonstrated a clear cytotoxic effect of low-dose Ara-C. The greater increase of granulopoietic cells within DC in the Ara-C exposed group than in control mice after the end of drug administration is, in addition, an indication for differentiation induction by this kind of Ara-C therapy.     

Are there ventricle-specific postnatal maturational differences in myocardial beta-adrenoceptors?

Newborn hearts have restricted functional reserve and variable responsiveness to inotropes that could be partly due to differences in myocardial beta-adrenoceptors (beta-AR). To clarify this issue, this study documented ventricle-specific changes in myocardial beta-AR density and affinity during postnatal maturation. In vivo left and right ventricle (LV and RV, respectively) biopsies were obtained from newborn (3-day-old, n = 11), immature (14-day-old, n = 7), and adult (n = 6) pigs. Total beta-AR density (B(max), fmol/g) and dissociation constant (K(d), pmol/L) were determined by radioligand binding with I125 iodocyanopindolol. Overall, beta-AR B(max) in the LV significantly decreased with maturation. Interestingly, newborn animal hearts (LV and RV) subdivided into 2 groups: an adult-like low K(d) group with low B(max) and a fetal-like high K(d) group with high B(max), which were significantly different from one another. The high K(d) newborn group also had significantly higher K(d) and B(max) than both immature and adult hearts. Newborns had similar Bmax but higher Kd in the LV than the RV, whereas immature and adult hearts did not have ventricular differences. During maturation, beta-AR density decreased, whereas LV beta-AR binding affinity increased. Variable beta-AR maturity was also identified immediately post partum, which could potentially explain the newborn heart's variable responsiveness to inotropes. The subset of newborn hearts with lower binding affinity (reduced responsiveness) could also contribute to the newborn heart's overall reduction in functional reserve.     

Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer?

Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers.KEY WORDS: Acute myeloid leukaemia, Cancer, Clonal evolution, In vivo models of leukaemia, Mutation     

Tumour antigen-targeted immunotherapy for chronic myeloid leukaemia: is it still viable?

In haematological cancers, malignant cells circulate in the blood and lymphatic system. This may make leukaemic cells easier to target by immunotherapy than in other types of cancer. Various immunotherapy strategies have been trialled in several leukaemias including chronic myeloid leukaemia (CML) and in general, these have been aimed at targeting tumour-associated antigens (TAA). There are numerous TAA expressed by CML patients including WT1, proteinase 3, BCR-ABL and HAGE amongst others. The immunogenicity of the CML-specific tumour antigen, BCR-ABL, has been the subject of much debate and its role in the development of the disease and its unique sequence spanning the breakpoint region make it an ideal target for immunotherapy. However, there are a limited number of immunogenic epitopes across the junctional region, which are restricted to only a few HLA types, namely A2, A3 and B7 (Clark et al. in Blood 98:2887–2893, 2001). The second CML-associated antigen is the helicase antigen HAGE, a cancer-testis antigen found to be over-expressed in more than 50% of myeloid leukaemias (Adams et al. in Leukaemia 16:2238–2242, 2002). Very little is known about the function of this antigen and its significance to CML. However, its membership of the DEAD-box family of ATP-dependent RNA helicases and the involvement of other members of this family in tumour cell proliferation (Eberle et al. in Br J Cancer 86:1957–1962, 2002; Yang et al. in Cell Signal 17:1495–504, 2005) suggest a crucial role in the RNA metabolism of tumour cells. For these reasons, HAGE also seems to be a good target for immunotherapy as it would be applicable for the majority of patients with CML. This review aims to discuss the potential of immunotherapy for the treatment of leukaemia, in particular CML, and the prospect of targeting three CML associated antigens: BCR, ABL and HAGE. During his career, Prof. Tony Dodi made a significant contribution in this area of leukaemia research, confirming the identity of immunogenic HLA-A3 and B7-restricted peptides as targets for CTL. Published, as a highlighted paper in Clark et al. (Blood 98:2887–2893, 2001), this study demonstrated the expression of MHC-peptide complexes on the surface of CML cells and the presence of tetramer-positive CTL activity in CML patients positive for these two HLA alleles. His drive and dedication for research excellence will be remembered by all who knew and worked with him. C. L. Riley and M. G. Mathieu are joint first authors and have contributed equally to this paper. This paper is a Focussed Research Review from the meeting which took place 28–29 May 2008 in Nottingham, UK, celebrating the contribution of Prof. I. A. “Tony” Dodi (+29.1.2008) to the EU project “Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumour immunology (ENACT)”. This review is dedicated to Prof. Tony Dodi (who passed away suddenly on 29 January 2008) and is written by colleagues who worked with him on research collaborations for more than 10 years. The paper deals with an area of research that Tony dedicated his working life to, that of leukaemia and immunotherapy. His contribution to this research was immense and he will be remembered for his drive, enthusiasm and passion for research excellence, which was infectious. Catherine Riley was Tony’s graduate student who successfully completed her doctorate degree, owing much to his wise direction and advice.     

Can systems biology approach help in finding more effective treatment for acute myeloid leukemia?

Acute myeloid leukemia (AML) is a hematological cancer comprising of cancer stem cells (CSCs) that are responsible for the disease progression, drug resistance and post treatment relapses. Advances in genomic technologies have identified AML as a genetically heterogenous disease with dysregulated gene expression networks. Furthermore, observation of intracellular signaling in individual CSCs by mass cytometry has demonstrated the dysregulation of the mitogen associated protein kinase (MAPK) pathways. It has been envisaged that the future treatment for AML would entail upon formulating individualized treatment plans leading to decreased drug related toxicities for patients. However the emerging role of signaling pathways as dynamic molecular switches influencing the cell cycle process, thereby leading to varying stages of cell differentiation, is making community rethink about the current strategies used for the treatment of AML. This commentary will focus on discovering novel biomarkers and identifying new therapeutic targets, to analyze and treat AML, on a platform enabled by systems biology approach.     

How is the relationship between TWIST-1 and BCR-ABL1 gene expressions in chronic myeloid leukaemia patients?

Background: The activation and increased expression of BCR-ABL1 lead to malignant chronic myelogenous leukaemia (CML) cells, as well as the resistance to antitumour agents and apoptosis inducers. Moreover, TWIST-1 protein is a prognostic factor of leukemogenesis, and its level is raised in CML patients with cytogenetic resistance to imatinib. So, there is a likely relationship between BCR-ABL1 and TWIST-1 genes.

Objective: The aim of the study was to assess the relationship between TWIST-1 and BCR-ABL1 expressions.

Methods: Peripheral blood samples were obtained from 44 CML patients under treatment and also from ten healthy subjects as normal controls. The expression of TWIST-1 and BCR-ABL1 genes was measured using real-time PCR, and ABL1 was used as the reference gene. The gene expression was evaluated by REST software.

Results: The expression levels of TWIST-1 and BCR-ABL1 genes in CML patients was changed 40.23?±?177.75-fold and 6?±?18-fold, respectively.

Discussion: No significant relationship was observed between the expressions of TWIST-1 and BCR-ABL1 genes. All patients with TWIST-1 expression levels?≥100-fold had failure of response to treatment.

Conclusion: The probability of the relationship between BCR-ABL1 and TWIST-1 is still debatable, and the average of TWIST-1 expression has been higher in patients without response to treatment. Definitive conclusion needs further investigations.     

Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

The hallmark of CML (chronic myeloid leukaemia) is the BCR (breakpoint cluster region)–ABL fusion gene. CML evolves through three phases, based on both clinical and pathological features: a chronic phase, an accelerated phase and blast crisis. TKI (tyrosine kinase inhibitors) are the treatment modality for patients with chronic phase CML. The therapeutic potential of the TKI imatinib is affected by BCR–ABL dependent an independent mechanisms. Development of MDR (multidrug resistance) contributes to the overall clinical resistance. MDR involves overexpression of ABC -transporters (ATP-binding-cassette transporter) among other features. MDR studies include the analysis of cancer cell lines selected for resistance. CML blast crisis is accompanied by increased resistance to apoptosis. This work reviews the role played by the influx transporter OCT1 (organic cation transporter 1), by efflux ABC transporters, molecules involved in the modulation of apoptosis (p53, Bcl-2 family, CD95, IAPs (inhibitors of apoptosis protein)], Hh and Wnt/β-catenin pathways, cytoskeleton abnormalities and other features described in leukaemic cells of clinical samples and CML cell lines. An MDR cell line, Lucena-1, generated from K562 by stepwise exposure to vincristine, was used as our model and some potential anticancer drugs effective against the MDR cell line and patients’ samples are presented.     

Could asynchrony in activity between the sexes cause intersexual social segregation in ruminants?

In many sexually dimorphic mammal species, the sexes live outside the mating season in separate social groups (''social segregation''). Social segregation occurs in a wide range of environmental conditions, but its cause in unknown. I suggest that social segregation is caused by a lower level of activity synchrony between individuals in mixed-sex groups than in single-sex groups, owing to sex differences in activity rhythm. As a consequence, mixed-sex groups are more likely to break up than single-sex groups, resulting in a predominance of single-sex groups at equilibrium. To test this hypothesis in red deer (Cervus elaphus L.), I developed an index of activity synchronization and showed that deer in mixed-sex groups were significantly less synchronized in their activity than deer in single-sex groups. Thus, low intersexual synchrony in activity can lead to social segregation. However, a lower level of intrasexual (female-female and male-male) activity synchrony within mixed-sex than within single-sex groups implies that additional factors (other than sex differences in foraging rhythm) contribute to the higher degree of instability of mixed-sex groups.     

Altered glyoxalase 1 expression in psychiatric disorders: cause or consequence?

Glyoxalase 1 is an enzyme, shown to protect against dicarbonyl glycation and the formation of advanced glycation end products. Recent findings suggest glyoxalase 1 as a molecular marker of psychiatric disorders. In clinical studies aberrant expression of glyoxalase 1 was shown to be involved in major depression, panic disorders and schizophrenia. In mouse models glyoxalase 1 was identified as a molecular marker of trait anxiety. However, anxiety-related behaviour in mice was inconsistently reported to correlate with elevated or reduced expression of glyoxalase 1. As yet, those findings were considered contradicting and the contribution of glyoxalase 1 to the aetiology of psychiatric disorders remained elusive. This review summarizes recent clinical and animal studies. In order to unravel the role of glyoxalase 1 in mental disease, findings are discussed with a particular focus on dicarbonyl substrate concentration. Prevailing the impact of dicarbonyl substrates on anxiety-related behaviour over the influence of glyoxalase 1 expression may consolidate findings that have been considered inconsistent. Taken together, this report suggests that physiological concentration of dicarbonyl compounds may differentiate a remedy from a poison.     

Radiotherapy in lung cancer. Mandatory or optional?

The purpose of the paper is to outline the current treatment strategies in lung cancer focusing on the possibile role of radiotherapy. METHOD: It defines the place of radiotherapy at the main histological types and stadiums proposing indications according to evidence based medicine. CONCLUSIONS: Radiotherapy is mandatory in non-operated NSCLC st. I-II in perioperative or palliative management of superior sulcus tumours; in the combined modality treatment of limited SCLC and in postoperative adjustment of resected single brain metastasis of lung cancer. It is optional after NSCLC segmentectomy; in palliation or postoperative adjuvation of NSCLC st. III Radiotherapy can be chosen as a part of best supportive care at NSCLC st. IV extensive SCLC and in case of multiple brain or localised lytic bone metastases.     

Emerging roles for lymphatics in acute kidney injury: Beneficial or maleficent?

Acute kidney injury, a sudden decline in renal filtration, is a surprisingly common pathology resulting from ischemic events, local or systemic infection, or drug-induced toxicity in the kidney. Unchecked, acute kidney injury can progress to renal failure and even recovered acute kidney injury patients are at an increased risk for developing future chronic kidney disease. The initial extent of inflammation, the specific immune response, and how well inflammation resolves are likely determinants in acute kidney injury-to-chronic kidney disease progression. Lymphatic vessels and their roles in fluid, solute, antigen, and immune cell transport make them likely to have a role in the acute kidney injury response. Lymphatics have proven to be an attractive target in regulating inflammation and immunomodulation in other pathologies: might these strategies be employed in acute kidney injury? Acute kidney injury studies have identified elevated levels of lymphangiogenic ligands following acute kidney injury, with an expansion of the lymphatics in several models post-injury. Manipulating the lymphatics in acute kidney injury, by augmenting or inhibiting their growth or through targeting lymphatic-immune interactions, has met with a range of positive, negative, and sometimes inconclusive results. This minireview briefly summarizes the findings of lymphatic changes and lymphatic roles in the inflammatory response in the kidney following acute kidney injury to discuss whether renal lymphatics are a beneficial, maleficent, or a passive contributor to acute kidney injury recovery.     

Altered complexin expression in psychiatric and neurological disorders: cause or consequence?

Complexins play a critical role in the control of fast synchronous neurotransmitter release. They operate by binding to trimeric SNARE complexes consisting of the vesicle protein Synaptobrevin and the plasma membrane proteins Syntaxin and SNAP-25, which are key executors of membrane fusion reactions. SNARE complex binding by Complexins is thought to stabilize and clamp the SNARE complex in a highly fusogenic state, thereby providing a pool of readily releasable synaptic vesicles that can be released quickly and synchronously in response to an action potential and the concomitant increase in intra-synaptic Ca(2+) levels. Genetic elimination of Complexins from mammalian neurons causes a strong reduction in evoked neurotransmitter release, and altered Complexin expression levels with consequent deficits in synaptic transmission were suggested to contribute to the etiology or pathogenesis of schizophrenia, Huntington's disease, depression, bipolar disorder, Parkinson's disease, Alzheimer's disease, traumatic brain injury, Wernicke's encephalopathy, and fetal alcohol syndrome. In the present review I provide a summary of available data on the role of altered Complexin expression in brain diseases. On aggregate, the available information indicates that altered Complexin expression levels are unlikely to have a causal role in the etiology of the disorders that they have been implicated in, but that they may contribute to the corresponding symptoms.     

Is it genomic imprinting or preferential expression?

Imprinted genes are monoallelically expressed in a parent-of-origin-specific manner, but for many genes reported to be imprinted, the occurrence of preferential expression--where both alleles are expressed but one is expressed more strongly than the other in a parent-of-origin-specific way--has been reported. This preferential expression found in genes described as imprinted has not been thoroughly addressed in genomic imprinting studies. To study this phenomenon, 50 genes, reported to be imprinted in the mouse, were chosen for investigation. Preferential expression was observed for 21 of 27 maternally expressed genes. However, only 5 of 23 paternally expressed genes showed preferential expression. Recently, it has been reported that a remarkable proportion of non-imprinted genes show differential allelic expression. If there is overlap between non-imprinted genes that are differentially expressed and imprinted genes that are preferentially expressed, we need to set new definitions of imprinted genes that, in turn, would probably lead to reassessments of the total number of imprinted genes in mammalian species.     

The protein phosphatase 2A regulatory subunit B55α is a modulator of signaling and microRNA expression in acute myeloid leukemia cells

We recently discovered that the protein phosphatase 2A (PP2A) B55α subunit (PPP2R2A) is under-expressed in primary blast cells and is unfavorable for remission duration in AML patients. In this study, reverse phase protein analysis (RPPA) of 230 proteins in 511 AML patient samples revealed a strong correlation of B55α with a number of proteins including MYC, PKC α, and SRC. B55α suppression in OCI-AML3 cells by shRNA demonstrated that the B subunit is a PKCα phosphatase. B55α does not target SRC, but rather the kinase suppresses protein expression of the B subunit. Finally, the correlation between B55α and MYC levels reflected a complex stoichiometric competition between B subunits. Loss of B55α in OCI-AML3 cells did not change global PP2A activity and the only isoform that is induced is the one containing B56α. In cells containing B55α shRNA, MYC was suppressed with concomitant induction of the competing B subunit B56α (PPP2R5A). A recent study determined that FTY-720, a drug whose action involves the activation of PP2A, resulted in the induction of B55α In AML cells, and a reduction of the B subunit rendered these cells resistant to FTY-720. Finally, reduction of the B subunit resulted in an increase in the expression of miR-191-5p and a suppression of miR-142-3p. B55α regulation of these miRs was intriguing as high levels of miR-191 portend poor survival in AML, and miR-142-3p is mutated in 2% of AML patient samples. In summary, the suppression of B55α activates signaling pathways that could support leukemia cell survival.