Dr. Bob Löwenberg (Editor-in-Chief) and Dr. Nancy Berliner (Deputy Editor-in-Chief) have combined efforts to identify some of the most outstanding Blood articles that have appeared either in print or online during the two-month interval between issues of The Hematologist. The citations are annotated to provide readers both with a concise description of the thrust of the article and an explanation of why the paper is particularly important. The goal is to underscore the remarkable research that is published in Blood and to highlight the exciting progress that is being made in the field.
JULY 25, 2013
Torikai H, Reik A, Soldner F, et al. Towards eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood. 2013. Epub ahead of print.
Long-term engraftment of allogeneic cells necessitates eluding immune-mediated rejection and is currently achieved by the combination of matching for human leukocyte antigen (HLA) expression and immunosuppression. Torikai and colleagues developed designer zinc finger nucleases (ZFNs) to selectively eliminate HLA expression as an approach to circumventing immune-mediated clearance of cells. The novel approach of genetic engineering for altering HLA expression on T cells or embryonal stem cells may ultimately prove useful in the development of banks of T cells or primitive stem cells that can be transplanted without being susceptible to clearance by allospecific T cells. Thus, the results provide a foundation whereby universal cells from one donor can be used for immunotherapy or stem cell transplant in multiple recipients.
Hahn CK, and Lowrey CH. Eukaryotic initiation factor 2α phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism. Blood. 2013;122:477-485.
Strategies to increase fetal hemoglobin (HbF) levels have the potential to ameliorate symptoms and improve the lives of β-hemoglobinopathy patients. While most studies have focused on induction of γ-globin gene expression, in the present study, the authors investigated whether increasing eukaryotic initiation factor 2α (eIF2α) phosphorylation, a key regulator of protein translation, could enhance HbF post-transcriptionally in human primary erythroid cells. Their results provide convincing evidence that fetal hemoglobin production can be significantly increased through translation, a mechanism that has not previously been targeted. Importantly, the increase in HbF observed was accompanied by a decrease in HbA. The magnitude of this effect of combined translational and transcriptional approaches can produce levels of HbF sufficient to significantly benefit most patients with β-hemoglobinopathies.
JUNE 13, 2013
Miyazaki Y, Fujiwara H, Asai H, et al. Development of a novel redirected T cell-based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia. Blood. 2013;121:4897-4901.
While adult T-cell leukemia (ATL) has a poor prognosis, the immune effect of allogeneic stem cell transplantation is potentially curative. However, an effective target for anti-ATL immunotherapy has yet to be defined. In the June 13 issue of Blood, investigators demonstrate for the first time that human telomerase reverse transcriptase (hTERT), a leukemia-associated antigen, is a promising target at which to aim genetically programed T cell to selectively recognize and kill ATL tumor cells. This paper provides proof of concept of the feasibility of developing selective immunotherapy for ATL by genetically redirecting antigen targeting of T cells.
MAY 30, 2013
Rajala HLM, Eldfors S, Kuusanmāki H, et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood. 2013;121:4541-4550.
Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. The STAT molecules have a major role in intracellular signaling. Recently, somatic mutations in the STAT3 gene were discovered in 30 to 40 percent of LGL leukemia patients. In this paper, investigators screened a remarkably large cohort of LGL patients for STAT5 mutations. By exome and transcriptome sequencing of two STAT3-mutation negative LGL leukemia patients and, subsequently, by targeted amplicon sequencing of 211 LGL leukemia patients, the authors identified four patients with recurrent, somatic missense mutations (Y665F and N642H) in the SH2 domain of the STAT5b gene. The Y665F and N642H mutant constructs increase both the transcriptional activity of STAT5 and the level of tyrosine (Y694) phosphorylation. The clinical course of the disease in patients with the N642H mutation is aggressive and fatal, clearly different from typical LGL leukemia, which has a relatively favorable outcome. This is the first time somatic STAT5 mutations have been discovered in human cancer. These findings further emphasize the important role of STAT family genes in the pathogenesis of LGL leukemia.
MAY 24, 2013
Yuan L, Janes L, Beeler D, et al. Role of RNA splicing in mediating lineage-specific expression of the von Willebrand factor gene in the endothelium. Blood. 2013;121:4404-4412.
Yuan and colleagues elucidate the role of RNA splicing in tissue-specific expression of von Willebrand factor (vWF) protein. This study confirms that the presence of the first intron of vWF is required for endothelial cell, but not megakaryocyte, expression of vWF. Interestingly, the intron could be replaced by heterologous introns without eliminating expression. In addition, the presence of the intron affected protein levels, not RNA levels. These discoveries suggest that the splicing process itself is important for post-transcriptional, tissue-specific expression of vWF. These fascinating insights into the molecular events regulating VWF gene expression may also provide clues to the pathogenesis of von Willebrand disease in patients who have divergent loss of expression between endothelial and platelet vWF.
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