Perspective Chapter: RNA Therapeutics for Cancers

RNA therapeutics represent a promising class of drugs and some of the successful therapeutics have been recently transformed into clinics for several disorders. A growing body of evidence has underlined the involvement of aberrant expression of cancer-associate genes or RNA splicing in the pathogenesis of a variety of cancers. In addition, there have been >200 clinical trials of oligonucleotide therapeutics targeting a variety of molecules in cancers. Although there are no approved RNA therapeutics against cancers so far, some promising outcomes have been obtained in phase 1/2 clinical trials. We will review the recent advances in the study of cancer pathogenesis associated with RNA therapeutics and the development of RNA therapeutics for cancers

Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity

A new mouse in which an IRES-GFP cassette is knocked-in to the Evi1 locus reveals that HSC long-term multilineage repopulating activity specifically segregates with expression of the Evi1 transcription factor

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Pathogenic Roles of RNA-Binding Proteins in Sarcomas

RNA-binding proteins (RBPs) are proteins that physically and functionally bind to RNA to regulate the RNA metabolism such as alternative splicing, polyadenylation, transport, maintenance of stability, localization, and translation. There is accumulating evidence that dysregulated RBPs play an essential role in the pathogenesis of malignant tumors including a variety of types of sarcomas. On the other hand, prognosis of patients with sarcoma, especially with sarcoma in advanced stages, is very poor, and almost no effective standard treatment has been established for most of types of sarcomas so far, highlighting the urgent need for identifying novel therapeutic targets based on the deep understanding of pathogenesis. Therefore, defining the network of interactions between RBPs and disease-related RNA targets will contribute to a better understanding of sarcomagenesis and identification of a novel therapeutic target for sarcomas

ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells

Summary: Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells. : The paucity and heterogeneity of CML stem cells are obstacles for analyses. In our study, a model of CML stem cells derived from CML-iPSCs identified ADAM8 as an antigen of TKI-resistant cells. In CML patients, ADAM8+ cells showed TKI resistance and residual CML cells after TKIs-treatment were concentrated in ADAM8+ population, suggesting that ADAM8 is a marker of TKI-resistant CML cells. Keywords: chronic myeloid leukemia, disease specific iPSCs, TKI-resistant CML stem cell

Successful treatment with recombinant thrombomodulin for B-cell lymphoma-associated hemophagocytic syndrome complicated by disseminated intravascular coagulation

金沢大学医薬保健研究域医学系We report here a 47-year-old male with the diagnosis of high-grade B-cell lymphoma and hemophagocytosis accompanying disseminated intravascular coagulation (DIC). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disorder, and LAHS secondary to B-cell lymphoma is relatively rare compared to that secondary to T- or NK/T-cell lymphoma in Western countries. T- or NK/T-cell LAHS is sometimes combined with DIC, which makes patients\u27 outcomes even worse, but few reports of B-cell LAHS accompanying DIC has been published so far. We successfully treated a patient with this condition with recombinant thrombomodulin (rTM), a novel agent for DIC. We believe that rTM is a therapeutic option in cases with B-cell LAHS accompanying DIC