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Inside the January and February 2014 issues

Posted By Connections Editor , Friday, February 28, 2014
Updated: Thursday, February 20, 2014

January 2014-inside this issue

#The role of stroma cells in MDS xenotransplantation

Li and Deeg, pages 410.

There has been a veritable explosion of information on genetic mutations in hematopoietic cells in patients with myelodysplastic syndromes (MDS). Concurrently, several murine models mimicking human MDS have been developed. However, studying the human disease invivo has remained challenging, mainly due to the difficulty of propagating CD34+ cells derived from patients with MDS in mice. There is considerable evidence that for MDS engraftment to be successful, certain microenvironment signals are required. This review by Li and Deeg summarizes data on murine xenotransplantation models of MDS with emphasis on the role of the microenvironment, specifically, stroma and mesenchymal cells. The authors describe strategies to improve engraftment that include, among others, genetic modification of mice to express human growth factors and administration of mesenchymal cells or stroma cells, either directly into the marrow cavity or intravenously. These studies have gained in interest due to the observations that nonclonal cells in the MDS marrow also show altered gene expression and function, presumably related to signals derived from the clone. An interesting byproduct of these studies is the observation that when coinjected intravenously with hematopoietic cells, stroma cells were able to reach bone marrow and spleen. However, none of the mice in the models described in this review have developed clinical features of human MDS, indicating that additional research is needed to generate fully developed MDS in these models. This comprehensive review draws attention to the interactions between marrow stroma and clonal hematopoietic cells in MDS and presents evidence to support the concept that MDS arises from hematopoietic stem cells.

#Mixing T cell development with seven-up

Ichim etal., pages 4658.

The Drosophila protein seven-up (svp) is a key regulator of cell fate decisions in neural development. Recent studies revealed that the orphan nuclear receptor Ear-2, a mammalian homologue of svp, plays a pivotal role at several stages of normal hematopoietic development, and it is an essential negative regulator of granulocytic differentiation in acute myelogenous leukemia. In this article, Ichim etal. investigated the role of Ear-2 in T cell development. They found that hematopoietic stem cells (HSCs) transduced to overexpress Ear-2 failed to repopulate the thymus when infused into lethally irradiated recipients. By using the OP9-DL1 stromal cell line, an invitro system of T cell differentiation, they documented two distinct defects in T cell development initiated with Ear-2-overexpressing HSCs. The first defect was detected at the DN1-DN2 stage, where they observed a severe reduction in proliferation, with widespread changes in the expression of genes associated with early T cell differentiation. The second defect was detected at the DN4 to DP transition, where they observed a block in differentiation accompanied by a wave of apoptosis–a defect identical to that seen in mice with targeted deletion of RORγt, another orphan nuclear receptor. The findings of Ichim etal. indicate that in addition to its roles in hematopoiesis and leukemia, Ear-2 is a novel negative regulator of T cell development, suggesting that this svp homologue may act as a brake in multiple transcriptional programs of differentiation. This discovery has important implications for future development of pharmacologic ligands aimed at regulating Ear-2 activity, which could offer a strategy for therapeutic modulation of both AML and T cell development.

#Memory T cells provide significant advantages for TCR-RNA based immunotherapy

Thomas etal., pages 2838.

Current strategies in cellular immunotherapy of cancer and viral infections include the adoptive transfer of T-cell receptor (TCR) and chimeric antigen receptor engineered T cells. When using transient TCR-RNA expression systems in clinical studies, multiple infusions with receptor-redirected T cells appear necessary. However, in allogeneic hematopoietic stem-cell transplantation, repeated transfer of donor-derived T cells increases the risk of inducing alloreactive graft-versus-host-disease. Considering this, Thomas etal. analyzed in this article alloreactivity of different human CD8+ T-cell subsets transfected with TCR-RNA. They observed in invitro studies that allo-reactivity developed significantly stronger in purified naive compared with memory or EBV-specific T-cell populations. Similar data were obtained after adoptive transfer of CD8+ T-cell subsets into a newly developed invivo alloreactivity test system, including immunodeficient NSG mice previously engrafted with human hematopoietic stem cells. This observation, along with strong effector function after TCR-RNA transfer, suggest CD8+ memory and EBV-specific T cells as promising tools for treating residual leukemia disease and viral infections after allogeneic transplantation.

#Transcriptional regulation of the hematopoietic hierarchy by microRNAs

Raghavachari etal., pages 14–27.

Hematopoiesis is a dynamic process that produces circulating blood cells of different lineages through the proliferation, differentiation, and maturation of self-renewing stem cells. Disruption in this well-orchestrated process leads to significant pathologic conditions including anemia, thrombocytopenia, lymphoma, and leukemia. Past studies have identified molecules such as lineage-specific cytokines and transcription factors as critical regulators of hematopoiesis. Recent technological advances in the analysis of noncoding RNAs have led to the understanding that miRNAs are powerful regulators of diverse cellular processes with critical roles in disease pathobiology. In this article, Raghavachari etal. examined the global expression of miRNA in the hematopoietic hierarchy to determine their regulatory roles in the lineage-specific commitment of stem cells. They detected 49 differentially expressed miRNAs, with functional roles in cellular growth, proliferation, and apoptosis during lineage-specific differentiation of stem cells. Target prediction analyses of these differentially expressed miRNAs identified potential miRNA targets associated with the hematopoietic differentiation process. Their integrated analysis of these potential mRNA targets confirmed most of them and provided a library of miRNA-mRNA networks including 87 highly correlated miRNA-mRNA pairs with functional roles in cellular growth and proliferation, hematopoietic system development, and Wnt/Beta-catenin and Flt 3 signaling pathways. This study provides strong evidence that miRNA molecules regulate the hematopoietic process. Future functional analysis of the differentially expressed miRNAs could result in the discovery of regulatory miRNA hubs, which in turn could lead to development of novel therapeutics for the treatment of hematopoietic disorders.

February 2014- inside this issue

#Lenalidomide, drug effect on angiogenesis in chronic lymphocytic leukemia

Maffei etal., pages 126136.

Lenalidomide is an immunomodulatory derivative (IMID) agent that is clinically active in patients with chronic lymphocytic leukemia (CLL). Increasing evidence suggest that angiogenesis can play a role in CLL pathophysiology, providing a supporting and protective milieu inside tissues. Although lenalidomide has been shown to affect angiogenesis invitro, little is known concerning its antiangiogenic properties in patients with CLL. In this study, Maffei etal. inspected the effect of lenalidomide on angiogenesis-related factors in 27 patients with relapsed or refractory CLL treated within a phase II clinical trial and invitro in a coculture system of endothelial and CLL cells. They demonstrated that lenalidomide exerts an antiangiogenic effect in treated patients by inhibiting the release of proangiogenic factors and by decreasing the number of circulating endothelial cells. Lenalidomide was reported to be effective in heavily pretreated or high-risk cytogenetics CLL patients, with response in 32%–47% of cases. The investigators identified vascular endothelial growth factor, bFGF levels, and the activation status of circulating endothelial cells as biological parameters associated with lenalidomide response. Of interest, Maffei etal. also report that lenalidomide interferes with CLL/endothelial cell crosstalk, reducing the survival advantage acquired by leukemic cells. This study provides a novel insight into the pleiotropic effects of lenalidomide in patients with CLL, including the disruption of the tumor-supporting properties ascribed to angiogenesis-related factors and endothelial cell contact. The identification of patients who respond to lenalidomide remains a challenging goal for clinicians. The work presented here indicates easily detectable parameters that could be useful to predict lenalidomide response.

#Pharmacologic activation of p53 impairs thrombopoiesis and leads to thrombocytopenia

Iancu-Rubin etal., pages 137145.

demonstrated to activate p53 and have promising anticancer effects in preclinical studies. RG7112 is the first clinically evaluated MDM2-p53 inhibitor that showed antitumor activities in several phase I clinical trials in solid tumors and hematologic malignancies. However, preliminary data indicate that one of the major hematologic toxicities associated with RG7112 administration in patients is thrombocytopenia. A number of studies in murine megakaryocytes and in human leukemic lines suggest that p53 has a role in megakaryopoiesis. In this study, Iancu-Rubin etal. used RG7112 as a pharmacological probe to activate p53 in human primary megakaryocytes to explore the role of p53 in normal megakaryopoiesis and to decipher the mechanisms responsible for RG7112-induced thrombocytopenia. They demonstrate that RG7112 treatment induces thrombocytopenia in rodents and primates and is deleterious for primary human megakaryopoiesis exvivo. RG7112 induced apoptosis of hematopoietic progenitors during the initial stages of megakaryocyte development and impaired their maturation during the later stages (i.e., inhibited DNA synthesis during megakaryocyte polyploidization and impaired demarcation membrane system formation and platelet granules biogenesis). The authors propose that these two mechanisms of action render the megakaryocytic lineage more susceptible to the drug and contribute to the development of RG7112-induced thrombocytopenia. Importantly, they show that the negative effects of RG7112 on normal thrombopoiesis are reversible, suggesting that intermittent therapeutic dosing of the drug might be a strategy for minimizing the degree of thrombocytopenia yet, retaining its antitumor effects. Furthermore, these studies provide a rationale for exploiting the inhibitory effects of RG7112 to reduce platelet counts in patients with myeloproliferative neoplasms.

#A classification system for hematopoietic stem cells based on reconstitution times

Ema etal., pages 74–82.

In this review, Ema etal. discuss the latest studies on hematopoietic stem cell (HSC) heterogeneity. The current classification systems of HSCs are based on their myeloid and lymphoid reconstitution ratios; however, Ema etal. propose a novel classification—LT-, IT-, and ST-HSCs—based on reconstitution times. They examine the relationship of the various classification systems and discuss how different HSC classes are related to one another in the hematopoietic hierarchy. The authors also make suggestions for how to design experiments based on their proposed classification system. Written by pioneers and leading figures in the field, the topic of this review is timely. The field has evolved quickly, and there is a need for review articles summarizing these new developments in a comprehensive way.

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