(WASHINGTON) – Welcome to “This Week in Blood,” a weekly snapshot of the hottest studies from each week’s issue of Blood, the official journal of the American Society of Hematology (ASH), hand-picked by Blood Editor-in-Chief Bob Löwenberg, MD, and Deputy Editor Nancy Berliner, MD. If you would like a PDF copy of any of the manuscripts highlighted below or would like to request an interview with the author, please email email@example.com.
EZH2 overexpression in natural killer /T-cell lymphoma confers growth advantage independently of histone methyltransferase activity, Yan et al.
The role of the oncogene EZH2 in cancer is complex and may vary depending on the cellular context. In this paper appearing this week in Blood, authors provide novel insights into the pathogenesis of natural killer/T-cell lymphoma (NKTL) and the role of EZH2 deregulation, and report that EZH2 is aberrantly overexpressed in the majority of NKTL cases. In this manuscript, the investigators establish that deregulation of EZH2 in NKTL provides a tumor growth advantage, show that EZH2 upregulation is mediated by MYC-induced repression of its regulatory miRNAs, and demonstrate that oncogenic EZH2 properties do not require a functional SET domain. The paper further demonstrates that mechanistically, EZH2 directly promotes the transcription of Cyclin D1 seemingly independent of its enzymatic activity. These studies identify not only a novel oncogenic role of EZH2 independent of its known methyltransferase activity, but they also suggest that targeting EZH2 may have therapeutic utility in patients with this type of lymphoma.
Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia, Rajala et al.
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 appearing this week in Blood, 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 identify 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 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 are discovered in human cancer. These findings further emphasize the role of STAT family genes in the pathogenesis of LGL leukemia.
IκB kinase (IKK) phosphorylation of SNAP-23 controls platelet secretion, Karim et al.
Platelet secretion plays a key role in controlling thrombosis, inflammation, angiogenesis, and other processes. The platelet secretory machinery offers a unique target to modulate hemostasis. Much of the protein machinery that mediates membrane fusion responsible for granule exocytosis in platelets has been described. However, the mechanism by which this machinery responds to platelet stimulation and the molecular routes leading to secretion in platelets remain largely unknown. This manuscript describes an entirely new pathway via IkappaB kinase (IKK) that phosphorylates SNAP-23, one of the major t-SNAREs, and subsequently leads to granule-plasma membrane fusion and platelet granule release. The fact that this pathway involves a nongenomic role for IKK is novel. Revealing IKK to be critical for regulation of secretion, through phosphorylation, is important because kinase inhibitors targeting this kinase are already developed. Pharmacologic inhibition or deletion of platelet IKK affects bleeding times. These kinase inhibitors may constitute new ways to modulate platelet function, hemostasis, and thrombosis, and this paper therefore constitutes an important advance in our knowledge.
Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field of hematology, is available weekly in print and online. Blood is the official journal of the American Society of Hematology (ASH) (www.hematology.org), the world’s largest professional society concerned with the causes and treatment of blood disorders.
ASH’s mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology.
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