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Inside the November and December 2013 Issues

Posted By Connections Editor, Tuesday, December 31, 2013
Updated: Monday, December 23, 2013

November 2013

#Heterospecific cell hybrids, a powerful system for the study of globin gene switching
See Chang etal., pages 967–979.

Heterospecific cell hybrids provide a useful cellular system to test the dynamic behavior of chromosomally transferred genes upon exposure to new cellular environments. Although the globin expression phenotype of chromosomally transferred human beta globin locus in heterospecific hybrids has been studied previously, the influence of established chromatin domains within the donor cells on the outcome of globin gene expression following chromosomal transfer is still not clear. The availability of cells with documented divergent chromatin states provided this opportunity, as described in this article by Chang etal. Through selective retention of the human chromosome 11 marked with a neomycin resistance gene, the authors created hybrids between human embryonic stem cells (hESCs) or hESC-derived erythroid cells and murine erythroleukemia (MEL) cells and performed long-term observations of the expression of specific human globin genes in the MEL environment. The authors report several interesting findings. First, the entire globin locus of hESCs was mostly inactive and resistant to DNaseI digestion, but when transferred to the adult environment of MEL cells, only beta globin became activated. Second, the epsilon and gamma globin genes of the hESC-derived erythroid cells were actively transcribed. Upon exposure to an adult environment, which is repressive for fetal or embryonic globins, the chromatin state of the epsilon globin gene changed from opened to closed, whereas that of the gamma globin genes remained open, despite the presence of specific gamma globin repressor proteins in the adult environment. Third, in the presence of fully active gamma globin genes, the beta globin gene was not activated within the adult environment, which is consistent with the competitive nature between the transcription of gamma and beta globin genes. However, after prolonged culture, there was a progressive switch from predominant gamma to predominant beta globin expression accompanied by remodeling of the chromatin landscape. This switching process was accelerated by the overexpression of the gamma globin repressor klf1 and partially reversed by the downregulation of Bcl11a in combination with decitabine treatment. Based on the sustained human gamma globin expression within the adult MEL transcriptional environment, the authors predict that erythoid-committed cells with high gamma expression, such as the hESC- or iPSC-derived erythroid cells, are not going to switch quickly upon transplantation into adult recipients. This interesting and important study provides important insights into the interplay between the transcriptional environment and chromatin architecture in governing globin gene expression, and it provides a powerful model system for further research at the molecular level.

#Harnessing redox homeostasis for enhanced hematologic recovery after hematopoietic stem cell transplantation
See An etal., pages 944–956.

Understanding the molecules that regulate hematopoietic reconstitution is essential to develop novel approaches for enhancing donor cell engraftment and reducing transplant-related mortality after hematopoietic stem cell (HSC) transplantation. In a previous report, this group demonstrated that AMD3100/plerixafor (a CXCR4 antagonist) enhanced engraftment and chimerism when administered after transplantation in mice. To determine whether this effect was due to the modulation of the microenvironment, the authors used a proteomic approach to identify proteins that are modulated by AMD3100 in the bone marrow supernatants of transplant recipients. They chose to focus on thioredoxin, a small oxidoreductase protein that was upregulated by AMD3100. The key role of thioredoxin in mammals is to function as an antioxidant or reactive oxygen species scavenger. Persistent oxidative stress is one of the major causes for HSC injury during total body irradiation and for graft-versus-host disease during HSC transplantation. The authors demonstrated that thioredoxin can mitigate radiation injury and enhance long-term repopulating HSCs when added to HSC cultures for only 24 hours or administred after transplant. They also showed that giving a combination of thioredoxin and AMD3100 after HSC transplantation promoted donor HSC reconstitution in the secondary transplant recipient mice. This study has important implications because it suggests that thioredoxin has the potential to overcome one of the major hurdles associated with HSC transplantation: delayed or failed donor cell engraftment. Furthermore, recombinant human thioredoxin is readily available and can be administered intravenously, offering the possibility of promptly translating these findings into clinical applications to improve the care and outcome of transplantation patients.

#Double umbilical cord blood transplantation for hematological malignancies
See Wallet etal., pages 924–933.

There are several features that make umbilical cord blood (UCB) a clinically beneficial source of hematopoietic stem and progenitor cells. UCB is abundantly available, and because it is an otherwise discarded material, its use presents no risk or discomfort for the donor. The risk of transmissible infectious diseases is much lower with UCB than with adult bone marrow donations. In addition, the immunologic immaturity of UCB cells allows transplantation in HLA-incompatible hosts and a decrease in the probability and the severity of acute and chronic graft-versus-host disease. However, the low number of hematopoietic stem and progenitor cells in single UCB collections represents a major drawback for its use in transplantation. To overcome this problem, several recent clinical investigations have focused on the use of double UCB for adult patients when cellularity in a single unit is not sufficient. In this study, Labussière Wallet etal. performed a multicenter study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry to evaluate the long-term outcomes after adult dUCB transplantation (dUCBT) for hematologic malignancies and to study the different parameters involved in the dominance of one UCB unit after transplantation. Among their findings, the authors report that after a median follow-up of 49.5 months, the 3-year probabilities of overall and progression-free survival were 41% and 35%, respectively. Importantly, they obtained a long-term plateau among patients with reduced intensity conditioning with a 3-years survival probability of 60%, which makes dUCBT a promising treatment strategy for these patients. Another interesting observation was that among patients transplanted with a male and female unit, there was a significant overall survival advantage when male cord engrafted male recipients, which suggests a dominant advantage in using male donor cells for male recipients. Gender has never been considered in previous analyses of dUCBT and needs to be studied in a larger cohort of patients.

December 2013

#Inhibition of GSK-3β promotes naive T cell expansion in bone marrow reconstituted mice.
See Shen etal., pages 1016–1027.

Hematopoietic stem cell transplantation (HSCT) is associated with a high risk of mortality, partially because of the harmful effects of the preconditioning myeloablative regimens. Pretransplant conditioning impairs thymic function, leading to delayed T cell regeneration. In addition, the thymus-independent expansion of mature T cell promotes their differentiation, limiting the diversity of T cell responses, which increases the risk of opportunistic infections and leukemia relapse. Thus, inhibiting the expansion of mature T cell could represent a promising therapeutic approach to improve immune reconstitution after transplantation. In this regard, the Wingless (Wnt) signaling represents a potential target, as it has been shown to inhibit mature T-cell differentiation in transgenic mouse models. In this manuscript, Shen etal. show that pharmacologic activation of Wnt increased the naive T cell pool in mice transplanted with human haematopoietic stem cells. Using a small molecule inhibitor of GSK-3β, 6-bromoindirubin 3’-oxime (BIO), they demonstrate that invitro BIO-treatment promoted naive T cell expansion following mitogenic stimulation and improved proliferative responses of T cells to allogeneic stimuli. Treatment with BIO expanded the IL7Rα+ subset of naive T cells and downregulated the expression of genes that were activated during effector cell differentiation and preserved naive T cell gene expression. The authors propose that pharmacologic inhibition of GSK-3β may increase the potency of T-cells in recipients of HSCT by expanding naive T cell subsets with diverse TCR repertoire, and therefore, significantly improve the outcome of HSCT in which impaired immunity is a serious cause of morbidity and mortality.

#Immunologic pathomechanism of Hodgkin’s lymphoma
See Jona etal., pages 995–1004.

Hodgkin’s lymphoma is a lymphoid malignancy of the immune system, and its cure-rate is one of the greatest success stories of hematology research. Its current first-line treatment gets 80–85% of patients tocomplete metabolic remission; however, treatment of primary refractory and relapsing patients remains challenging. Hence, a deeper understanding of its pathomechanism is needed. This review by Jona etal. provides a comprehensive cross-section of the current knowledge of the molecular mechanisms involved in Hodgkin’s lymphoma pathogenesis and progression. The authors put special emphasis on the immunologic processes and highlight recent therapeutic regimes aimed at improving treatment outcome and reducing late toxicities. This review targets hematologists and research scientists with interests in immunology and experimental hematology. The comprehensible writing allows readers who are new to the field to grasp the complex mechanisms involved in HD pathogenesis.

#Tenascin C regulates hemopoiesis within alternate niches
See Ellis etal., pages 1050–1061.

Microenvironments where hemopoietic stem and progenitor cells develop and reside require further elucidation. Recently, Nakamura-Ishizu etal. (2013) demonstrated that the extracellular matrix molecule Tenascin-C (TNC) was vital in hematopoietic regeneration within the bone marrow (BM) microenvironment. This article by Ellis etal. furthers our understanding of TNC in hemopoiesis by showing that TNC is not only important to steady-state homeostasis within the BM but also plays a role in regulating hemopoiesis within alternate niches such as the thymus. The authors show that TNC knockout mice had a higher proportion of mature T cells within the BM during both steady-state and post--long-term transplant, suggesting a role for TNC in lineage commitment. A decrease in the incidence and total number of thymic progenitor populations with a redistribution of early thymic progenitors to other organs indicated an additional role for TNC in migration and adhesion. Migration was further assessed through short-term homing assays, and evidence for TNC’s role as a cytoadhesive molecule was provided through mobilization assays. Analysis also suggested the integrin α9β1 was integral in these processes. Collectively, the data demonstrate the importance of TNC in steady-state hemopoiesis and highlights this glycoprotein as an important component of hemopoietic stem and progenitor cell niches. By better understanding stem cell niches, we will not only have a better understanding of normal blood formation and the etiology of blood diseases, but also of how to manipulate such niches for improved therapeutic outcomes.

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