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Inside the March and April 2013 Issues

Posted By Connections Editor, Wednesday, April 24, 2013
Updated: Wednesday, April 24, 2013

Take a quick tour of the January and February issues and get a feel for the publication's cutting-edge scientific content. Read the full issues online.

In this Issue – March 2013

#The mitochondrial redox environment during erythroid development affects mitochondria-less mature red blood cells
Mohanty et al.

Manganese superoxide dismutase (SOD2) maintains a low oxidative environment in mitochondria by converting toxic superoxide free radicals to hydrogen peroxide. Mature red blood cells (RBCs) do not contained SOD2 protein as they do not possess mitochondria, however; its deficiency or malfunction during erythroid development results in lasting changes to the mature RBC. In this manuscript, Mohanty et al. used an established hematopoietic specific SOD2 knockout mice chimera model to study the effect of SOD2 deficiency on two characteristics of RBCs: deformability and oxidative stress levels. They report that SOD2-/- RBCs have reduced deformability, higher amounts of heme degradation products, and a higher rate of hemoglobin oxidation compared to controls. These changes may explain the reduced RBC lifetime in circulation leading to increased RBC loss, which is associated with the anemia phenotype previously reported in these mice. These results support and expand the findings published by Case et al. in December 2012 in Free Radic Biol Med, which show that the disruption of the superoxide balance within the mitochondria leads to improper heme formation, gene regulation, and erythrocyte development. . Oxidative stress has been linked to sideroblastic, hemolytic and sickle cell anemia, and thalassemia. Studies such as these ones that further the understanding of how the mitochondrial redox environment affects RBC physiology may lead to novel therapies for those diseases.

#Acute lymphoblastic leukemia cells come out of the bone marrow protective niche for increased sensitivity to chemotherapy
Welschinger et al.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and represents 20% of adult acute leukemias. Despite good initial responses to combination chemotherapy, remission remains a significant problem. This lack of efficacy of therapy can be partly attributed to the protection provided to the leukemia cells by the bone marrow (BM) microenvironment, and thus, there is a lot of interest in finding therapies to get the cells out of this protective niche. However, the BM microenvironment also enhances the survival of normal hematopoietic stem and progenitor cells (HSPCs), making it important to determine whether mobilizing therapy by itself or in combination with chemotherapy increases toxicity towards these cells. The interaction of the cytokine SDF-1 with the CXCR4 receptor on the surface of HPSCs and leukemic cells has been implicated in the retention of normal and leukemic cells in the BM, and in this study by Welschinger et al., the authors show that inhibition of the interaction by the CXCR4 antagonist plerixafor (AMD3100) results in the mobilization of ALL cells from the BM and spleen for a longer period of time than normal HSPCs. Unlike what has been reported with acute myeloid leukemia cells, mobilization of ALL cells is associated with increased cell cycle activity, which may be capitalized upon by combination with chemotherapy, as demonstrated by increased survival of ALL xenografts treated with a combination of vincristine and AMD3100. This clinically important information can be leverage to design clinical trials to test the combined use of chemotherapy with AMD3100 for maximal effect on leukemic as opposed to normal hematopoietic cells. Such clinical trials will bring new hope to patients with relapsed or high-risk ALL.

#Mechanistic insights provide scientific justification for the use of Histone Deacetylase Inhibitors in Myeloproliferative Neoplasms
Gao et al., and Caldaza et al.

Philadelphia-negative myeloproliferative neoplasms (MPNs) are a collection of clonal hematological malignant diseases in which more than 50% of patients carry a single mutation (V617F) in the autoinhibitory region of the JAK2 tyrosine. This has lead to the presumption that aberrant gene expression controlled by the deregulated JAK2/STAT pathway is the main cause underlying the disease pathobiology. However, clinical trials with different JAK2 kinase inhibitors have not yet shown eradication of the malignant clone, warranting the search for alternative targets for therapy. Recently, studies have revealed a number of epigenetic alterations that also likely contribute to the pathogenesis of MPNs and determine clinical outcome. Indeed, abnormal histone deacetylase activity has been noted in MPNs and provides a rationale for treatment with Histone deacetylase inhibitors (HDACi). However, the extent and specific role of histone deacetylase-mediated epigenetic aberrations in MPN are still poorly understood. Two articles published in this issue of ExpHem provide mechanistic rationales for the use of HDACi in the treatment of MPN, either alone or in combination with existing therapies.

The article by Gao et al. sheds light on the mechanism of action of the HDACi sodium butyrate (SB) on the JAK/STAT signaling pathway in MPNs. SB is a short-chain fatty acid that induces the accumulation of acetylated histone leading to cell cycle arrest, differentiation and apoptosis in various cancer cells. In this study, the authors found that SB downregulates the JAK/STAT signaling through upregulation of the suppressors of cytokine signaling (SOCS)1 and 3, both of which are potent feedback inhibitors of JAK2/STAT signaling. Their Chip analysis links the downregulation of SOCS1 and 3 to the accumulation of acetylated histones on the genes’ promoter, which is potentially mediated by HDAC8, as demonstrated in a selective siRNA knockdown experiment. Confirmation of these findings is important; if HDAC8 inhibition alone is enough to cause cell death or colony formation inhibition of MPN cells, this concept can be utilized to address the off-target toxicities associated with the utilization of pan-HDAC inhibitors in MPN patients.

The manuscript by Caldaza et al. provides a scientific rationale for combination therapy of the pan-HDACi Givinostat (ITF2357, GVS) and hydroxyurea (HU) for the treatment of MPN patients. GVS has been shown to specifically inhibit proliferation of cells bearing the JAK2V617F mutation and has demonstrated significant activity with good tolerability in clinical studies in MPN. Moreover, a randomized Phase II clinical trial of GVS and HU has recently been completed and has indicated a favourable clinical activity of the combination of these two compounds in the treatment of Policytemia Vera patients. In this study, the authors used MPN cell lines and patients’ cells to demonstrate that a low dose of the two drugs induces synergistic apoptosis, what they link to the inhibition by HU of GVS-mediated induction of p21 and to increased caspase-3 activity. This timely manuscript clarifies the mechanism of the drugs' synergy at the cell cycle and molecular level and provides a scientific justification to their use as combination therapy for the treatment of MPNs.

In this Issue – April 2013

#Gene Set Control Analysis, a new bioinformatic tool to enhance our understanding of blood cell differentiation
Joshi et al.

Transcription factors (TFs) have the unique property that they recognise specific DNA sequence motifs, and therefore have the ability to decipher gene regulatory information encoded in our genome sequence. Recent technological breakthroughs in sequencing technology have made the generation of genome-wide transcription factor binding maps almost routine. However, it is still largely unclear how transcription factor proteins "read” regulatory information when they interact with our genomes. Progress in this area will be vital to enhance our understanding of blood cell differentiation, and, given the complexity and scale of genome-scale binding maps, is likely to depend on new bioinformatic data integration and analysis tools. The paper by Joshi et al reports the generation of a TF binding map compendium, where 142 publicly available datasets for both normal and leukemic murine blood cell types have been re-analysed, integrated and analysis results made available for use by the wider research community ( In addition, the group also report the development of a new bioinformatic web-tool, called Gene Set Control Analysis (GSCA). Experimental biologists commonly generate gene lists, such as differentially expressed genes, from a treatment/control microarray experiment. Such lists are then scrutinized for functional or pathway enrichment by, for example, gene ontology analysis. The new GSCA tool utilises the integrated 142 transcription factor binding maps to predict likely transcriptional regulators for any gene set of interest. Using GSCA, the authors predicted the reactivation of blood stem cell control mechanisms as a likely contributor to LMO2 driven leukemia, and also clarified the recent debate on the role of Myc in leukemia stem cell transcriptional programs. The GSCA tool is freely available, and a web interface for use by the wider community can be found at GSCA accepts both mouse and human gene lists for the prediction of likely upstream regulators. It is anticipated that the underlying compendium will grow further as the community generates ever-increasing numbers of transcription factor binding maps. Nevertheless, even in its current incarnation it is hoped that GSCA will be recognised by the community as a valuable new tool in the bioinformatic toolbox available to us all; hopefully it will increase our ability of extracting biological knowledge from genome-scale datasets.

#Novel strategy to generate engineered T cell precursors for immunotherapy
Liu et al.

Adoptive T-cell immunotherapy appears promising to treat T cell immunodeficiency or to improve immune reconstitution after hematopoietic stem cell transplantation. In addition, adoptive transfer of peripheral T cells engineered to express a tumor antigen-specific T cell receptor (TCR) presents a new approach to selectively target malignant cells. Despite recent advances in both stem cell and lymphocyte manipulations, these experimental approaches still have several limitations, particularly in optimal and safe generation, as well as expansion of specific T cell from TCR-transduced stem cells. In this study, Liu et al present a novel strategy for the manipulation of early stage T lymphopoiesis using a two step co-culture system. They show that TCR-transduced hematopoietic progenitors co-cultured on telomerized stromal cells in the presence of SCF, Flt3L and TPO, followed by co-culture on Delta-1- and -4-expressing stromal cells, produce pre-T cell precursors that have the potential to proliferate and differentiate. This study highlights the potential value of engineered human stromal cells to manipulate early T cell development for clinical application, and provides a culture system that could help accelerate the translation of the next generation of adoptive T-cell therapies to the clinical setting.

#Cord blood-derived MSC: a potential tool to accelerate bone marrow recovery after ionizing radiation
Shim et al.

Mesenchymal stem cells (MSCs) have a great capacity for self-renewal while maintaining their multilineage differentiation potential, making them a promising tool for tissue repair. Compared with bone marrow MSCs, human umbilical cord blood-derived MSCs (hUCB-MSCs) are easy to obtain without harm to the donor and have a faster proliferation rate. In this study by Shim et al, the authors investigate the potential of hUCB-MSCs to improve the recovery of hematopoiesis after total body irradiation in comparison with the well-studied agent granulocyte colony stimulating factor (G-CSF). Using sub-lethally irradiated mice, they show that hUCB-MSCs treatment significantly increased the number of peripheral leukocyte counts following a radiation dose for which G-CSF treatment was unsuccessful. Moreover, at some post-irradiation intervals, hUCB-MSCs treatment was more effective than G-CSF in supporting proliferation of various cells in the BM and, in contrast with G-CSF, modulated the plasma level of hematopoietic cytokines. Together, these observations show that hUCB-MSCs treatment is superior to G-CSF, providing support for their use in the treatment of ionizing radiation-induced bone marrow injury. In addition, this study has important implications in the clinical setting, in which hCB-MCSs could be used to accelerate bone marrow recovery after chemotherapy and especially after hematopoietic stem cell transplantation.

#A modified high dose cyclophosphamide regime that could lower the cost of treatment of patients with several aplastic anemia
Zhang et al.

Aplastic anemia (AA) is a potentially fatal disease characterized by depletion of hematopoietic precursors in bone marrow (BM). The standard therapy for patients with this disease who are not candidates for an allogeneic BM transplantation is immunosuppression with a combination of horse-antithymocyte globulin (ATG) and cyclosporine A (CsA). This treatment results in good overall survival rates. However, relapses and event-free survival are still not satisfying. Furthermore, horse-ATG is not routinely available in developing countries and the costs for ATG-preparations in general are substantial. Therefore, alternative treatments are urgently needed. In this context, this manuscript by Zhang et al reports a retrospective study of patients with severe or very severe AA that received either a modified high dose cyclophosphamide (HD-CTX) regime with CsA or a therapy with rabbit-ATG in combination with CsA. Both treatment groups showed comparable response rates, survival rates and toxicities. In previous clinical trials, HD-CTX showed promising remission rates but unacceptable toxic effects. In this regard, this is a notable study that shows that a lower dose of CTX might overcome the immense toxic effects of the conventional high dose regime. Importantly, the modified HD-CTX plus CsA therapy is significantly cheaper than the ATG plus CsA therapy, thus providing an affordable treatment alternative for severe AA patients that cannot afford ATG therapy. This preliminary study merits further investigation in well-designed, prospective, and randomized clinical trials.

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