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Inside the September and October 2013 issues

Posted By Connections Editor, Friday, November 1, 2013
Updated: Sunday, October 27, 2013

Inside this issue-September 2013

#Cohesin: a master regulator of hematopoietic transcriptional programs

See Panigrahi et al., pages 967–973.

The role of cohesin in mediating chromosomal cohesion between sister chromatids is well established. Recent evidence supports its role as a transcription regulator, as it is able to communicate with tissue-specific transcription factors and basal transcription machinery, mediate architectural chromatin organization, and communicate with chromatin remodeling

and modification molecules. In this review, Panigrahi et al suggested that cohesin may have a central role in the orchestration of hematopoiesis as a ‘‘master regulator’’ of transcriptional programs because of its ability to regulate transcription by various pathways. It will be very interesting to further understand how cohesin accomplishes such a complex process of orchestration of hematopoiesis.

#Tissue-specific T-regs: potential prognostic markers for acute graft-versus-host disease

See Engelhardt et al., pages 974–982.

Acute graft-versus-host disease (aGVHD) is a frequent life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Reliable diagnostic and prognostic markers that can predict incidence and survival are urgently needed. Regulatory T cells (T-regs) are a subset of CD4+ T cells capable of suppressing alloimmune responses. In this study, Engelhardt et al reported that after allo-HSCT, patients with high frequencies

of circulating skin (CLA+) or gut tissue-specific (a4b7+) T-regs at engraftment, had significantly lower incidence of aGVHD of skin and gut at day 100. They also had better overall survival and nonrelapse mortality at 2 years. Flow cytometric quantitation of tissue-specific T-regs is a relatively simple test, yet has the potential to be a powerful tool for the clinicians. It will guide them to implement early and aggressive tissue-specific pre-emptive therapies resulting in a decrease in the incidence of clinical aGVHD and improve outcomes in these patients.

#The unexpected role of Pbx3 in leukemic transformation

See Novak et al., pages 1016–1027.

Transgenic mice expressing NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) oncogenic fusion genes develop AML with a long latency and incomplete penetrance, and therefore, they are useful models to search for collaborating genetic events required for leukemic transformation. In this study, Novak et al showed that both CA10- and NHD13-induced AML acquired a Ras pathway mutation, whereas Flt3 mutations were documented only in CA10-induced AML. Moreover, some Hox genes (Hoxa5, Hoxa9, and Hoxa10 in particular) and mir196b (embedded within the Hoxa locus) were markedly upregulated in both NHD13 and CA10 mice. Interestingly, the Hox cofactors were differentially expressed, Meis1 was increased in CA10- induced AML, whereas Pbx3 was increased in NHD13-induced AML. Furthermore, the investigators demonstrated that loss of Pbx3 is important to the maintenance and survival of cells overexpressing an NHD13 fusion, an unexpected functional role for Pbx3 expression in NHD13-induced leukemic transformation. Such studies searching for collaborating events in leukemic transformation are valuable as they help identify novel therapeutic targets in AML.

Inside this issue-October 2013

#Burst-forming unit–erythroid assays in bone marrow failure

See DeZern et al., pages 808–816.

Patients with cytopenias and a cellular bone marrow (BM) can be a diagnostic and a therapeutic challenge, especially when there is no gross tumor, non-diagnostic morphology, and a normal karyotype. Previous reports have suggested a role for progenitor assays as potentially useful tests for diagnosis and predicting response to therapy. The utility of these assays lies in their ability to provide an assessment of BM growth and differentiation, which other BM tests cannot reliably offer. In this study by DeZern et al, 48 consultative cases of single or multi-lineage cytopenias with cellular marrows had aspirates sent for Burst-forming unit–erythroid (BFU-E) to aid in diagnosis. The data suggest that low BFU-E growth (less than 10 BFU-E /105 cells) is more consistent with a diagnosis of myelodysplastic syndrome (MDS) and helps to exclude the diagnosis of red cell aplasia, large granular lymphocytosis, or cytopenias from systemic autoimmune diseases. More robust BFU-E growth (20 BFU-E per 105 cells) is usually associated with external suppression of hematopoiesis, which occurs in non-large granular lymphocytosis, red cell aplasia, or autoimmunity. In this cohort, non-malignant diseases were well-distinguished from MDS by BFU-E growth. These findings suggest that the BFU-E assay could be a vital clinical adjunct for the patient and the clinician. In clinical settings with cytopenias of unclear significance, this assay may prove particularly useful for further differentiation of the etiology of the BM failure. Future prospective trials may be warranted to incorporate the BFU-E assays into the diagnostic algorithm for BM failure.

#Ciclopirox inhibition of mTOR provides a potential new approach to targeting AML

See Sen et al., pages 799–807.

Acute myelogenous leukemia is initiated and maintained by a chemoresistant population of cells known as leukemia stem cells (LSCs). Parthenolide (PTL) has been described as a selective agent that targets LSCs via inhibition of NF-kappaB and induction of reactive oxygen species (ROS). However, PTL treatment has also been shown to activate the mTOR pathway. The current study by Sen et al. demonstrates that the antifungal drug ciclopirox synergizes with PTL, resulting in potent antileukemia activity against blast, progenitor and LSC populations. This activity was mediated by the ability of ciclopirox to inhibit mTOR, an activity not previously described for this agent in AML. The study also demonstrates the importance of combinatorial strategies to overcome cytoprotective mechanisms. These findings provide a rationale for the use of ciclopirox in clinical trials and in combination therapies that may be improved by inhibition of mTOR.

#A chimeric lentiviral vector for both human and non-human primates hematopoietic repopulating cells

See Uchida et al., pages 779–788.

Innate immune factors, such as TRIM5a and cyclophilin A (CypA), act as major elements restricting retroviral infection among species and potentially limit transduction with retroviral vectors. When HIV1 infects human cells, HIV1 capsid binds to human CypA to escape from human TRIM5 a restriction. However, in rhesus cells, the mismatch between HIV1 capsid and rhesus CypA is recognized by rhesus TRIM5 a and prevents infection, and thus, transduction by HIV1-based lentiviral vectors. To circumvent the mismatch, Uchida and colleagues previously developed a chimeric HIV1 vector (cHIV vector) in which the HIV1 capsid is substituted with the simian immunodeficiency virus (SIV) capsid. The cHIV vector system successfully allowed for the evaluation of HIV1-based vector constructs in non-human primates, an important model in the development of clinical gene therapy trials. Their next question addressed in this study was whether the cHIV vector efficiently transduces human cells, because theoretically, the mismatch between human CypA and SIV capsid in the cHIV vector could be recognized by human TRIM5 a. Expectedly, the cHIV vector produced lower transduction efficiency in a human lymphoblast cell line compared to an HIV1 vector. However, both cHIV and HIV1 vectors showed similar transduction efficiency in human CD34+ cells in vitro and in humanized xenograft mice. In addition, they demonstrated that the cHIV vector is independent of human CypA in escaping from TRIM5 a restriction. These data indicate that the preclinical evaluation of lentiviral vectors targeting human hematopoietic stem cells can be performed using cHIV vectors in the non-human primate.

#The role of the microenvironment during fetal hematopoieisis

See Cao et al., pages 761–768.

Hemopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Recent studies in adult bone marrow(BM) have made significant advances in identifying important niche supportive cell types and extracellular components that are critical for HSC regulation. However, the understanding of the role of the microenvironment in the establishment of definitive HSCs and their expansion and maintenance during embryonic development is extremely limited. This review by Cao et al. examines the niche from a developmental perspective and highlights several important issues that merit further study. The

authors focus on the current knowledge of the components of each HSC microenvironment at various developmental stages and their known functional roles. They describe the cells, extracellular matrix, cytokines and signaling pathways that have been identified in different developing hemopoietic organs as well as in the adult BM. The review conveys the message that the microenvironment plays an important part in educating HSCs and modifying hematopoiesis throughout development. Indeed, fetal niches have unique properties, allowing the quick expansion of HSC during early gestation, and assisting in fetal hemopoietic migration during late gestation. Contrary to adult BM, many current studies assessing fetal niches are still reliant on in vitro stromal cell cultures, with the identification of specific cell types and molecular mechanisms regulating fetal HSC needing further investigation. Since reprogramming cells mimic fetal HSC behavior rather than adult HSC, understanding the mechanisms involved in fetal HSC regulation should lead to a better understanding of the mechanisms regulating pluripotency and thus facilitate the engineering of hematopoietic specification.

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