Mechanistic insights into lethal hyper progressive disease induced by PD-L1 inhibitor in metastatic urothelial carcinoma.

Hyper progressive disease (HPD) is a paradoxical phenomenon characterized by accelerated tumor growth following treatment with immune checkpoint inhibitors. However, the pathogenic causality and its predictor remain unknown. We herein report a fatal case of HPD in a 50-year-old man with metastatic bladder cancer.

Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization.

DNA hypomethylating agents (HMAs) are used for the treatment of myeloid malignancies, although their therapeutic effects have been unsatisfactory. Here we show that CRISPR-Cas9 screening reveals that knockout of topoisomerase 1-binding arginine/serine-rich protein (TOPORS), which encodes a ubiquitin/SUMO E3 ligase, augments the efficacy of HMAs on myeloid leukemic cells with little effect on normal hematopoiesis, suggesting that TOPORS is involved in resistance to HMAs. HMAs are incorporated into the DNA and trap DNA methyltransferase-1 (DNMT1) to form DNA-DNMT1 crosslinks, which undergo SUMOylation, followed by proteasomal degradation.

Knockdown of CDX2 Induces microRNA-221 Up-regulation in Human Colon Cancer Cells.

Background/aim: Caudal-type homeobox transcription factor 2 (CDX2) is a master regulator of intestinal development and maintenance of the intestinal epithelium. We previously revealed that CDX2 colorectal cancers (CRCs) were associated with poor survival and differential response to adjuvant chemotherapy. MicroRNAs (miRNAs), a class of non-coding RNAs typically composed of fewer than 25 nucleotides, are known to regulate gene expression and signaling pathways.

Metabolic reprogramming regulated by TRAF6 contributes to the leukemia progression.

TNF receptor associated factor 6 (TRAF6) is an E3 ubiquitin ligase that has been implicated in myeloid malignancies. Although altered TRAF6 expression is observed in human acute myeloid leukemia (AML), its role in the AML pathogenesis remains elusive. In this study, we showed that the loss of TRAF6 in AML cells significantly impairs leukemic function in vitro and in vivo, indicating its functional importance in AML subsets.

SRSF2 plays an unexpected role as reader of mC on mRNA, linking epitranscriptomics to cancer.

A common mRNA modification is 5-methylcytosine (mC), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of mC and impaired SRSF2 mC binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in mC recognition and the impact of the prevalent leukemia-associated mutation SRSF2.

An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress.

Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRAS expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRAS-induced replication stress to expand replication stress-tolerant cells (RSTCs).

[RNA splicing dysregulation in hematological malignancies].

Recurrent mutations in genes encoding key splicing factors, SF3B1, SRSF2, U2AF1, and ZRSR2 have been found in a variety of cancers, particularly in hematologic malignancies, including myelodysplastic syndromes, chronic myelomonocytic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia. Global mis-splicing of mRNAs targeted by aberrant splicing factors partly contributes to leukemogenesis through decrease protein expression of tumor suppressors and epigenetic modifiers, caused by mRNAs degradation of aberrantly spliced. Some of the mis-spliced mRNAs influence intracellular oncogenic pathways and cellular processes through a dysregulated expression of associated proteins, whereas others influence the function of co-mutated genes such as aberrant transcriptional regulators.

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.

Aberrant RNA splicing and therapeutic opportunities in cancers.

There has been accumulating evidence that RNA splicing is frequently dysregulated in a variety of cancers and that hotspot mutations affecting key splicing factors, SF3B1, SRSF2 and U2AF1, are commonly enriched across cancers, strongly suggesting that aberrant RNA splicing is a new class of hallmark that contributes to the initiation and/or maintenance of cancers. In parallel, some studies have demonstrated that cancer cells with global splicing alterations are dependent on the transcriptional products derived from wild-type spliceosome for their survival, which potentially creates a therapeutic vulnerability in cancers with a mutant spliceosome. It has been c.

Structural basis of cytokine-mediated activation of ALK family receptors.

Anaplastic lymphoma kinase (ALK) and the related leukocyte tyrosine kinase (LTK) are recently deorphanized receptor tyrosine kinases. Together with their activating cytokines, ALKAL1 and ALKAL2 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development, cancer and autoimmune diseases. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain, consistent with a metabolic role for Drosophila ALK.

Efficient production of human neutrophils from iPSCs that prevent murine lethal infection with immune cell recruitment.

Neutrophils play an essential role in innate immune responses to bacterial and fungal infections, and loss of neutrophil function can increase the risk of acquiring lethal infections in clinical settings. Here, we show that engineered neutrophil-primed progenitors derived from human induced pluripotent stem cells can produce functional neutrophil-like cells at a clinically applicable scale that can act rapidly in vivo against lethal bacterial infections. Using 5 different mouse models, we systematically demonstrated that these neutrophil-like cells migrate to sites of inflammation and infection and increase survival against bacterial infection.

Loss-of-function mutations in BCOR contribute to chemotherapy resistance in acute myeloid leukemia.

Primary refractory acute myeloid leukemia (AML) is unresponsive to conventional chemotherapy and has a poor prognosis. Despite the recent identification of novel driver mutations and advances in the understanding of the molecular pathogenesis, little is known about the relationship between genetic abnormalities and chemoresistance in AML. In this study, we subjected 39 samples from patients with primary refractory AML to whole-exome and targeted sequencing analyses to identify somatic mutations contributing to chemoresistance in AML.

Physical interaction between BAALC and DBN1 induces chemoresistance in leukemia.

BAALC is identified as a leukemia-associated gene and is highly expressed in CD34-positive hematopoietic stem cells. High BAALC expression is associated with poor prognosis in several types of acute myeloid leukemia. We explored binding partner proteins of BAALC by means of mass spectrometry and analyzed biological properties of BAALC-expressing leukemic cells.

[Aberrant RNA splicing and development of hematological malignancies].

Dysregulation of pre-mRNA splicing and transcription is a key step in gene expression control in patients with leukemia. Herein, we discuss the occurrence of frequent overlap of mutations affecting epigenetic regulation and pre-mRNA splicing in patients with leukemia, which together promote leukemogenesis through coordinated effects on the epigenome and pre-mRNA splicing. In particular, we have determined an important pathogenic role of cross-talk between altered epigenetic state and pre-mRNA splicing, provided functional evidence that mutations in pre-mRNA splicing factors drive leukemia development, and uncovered spliceosomal changes as a novel mediator of IDH2 mutant leukemogenesis.

Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization.

Although mutations in the gene encoding the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here, we characterize 98 tumors and 12 isogenic cell lines harboring hotspot mutations, identifying hundreds of cryptic 3' splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common mutation activates MYC via effects conserved across human and mouse cells.

Nationwide epidemiological survey of familial myelodysplastic syndromes/acute myeloid leukemia in Japan: a multicenter retrospective study.

Although several pedigrees of familial myelodysplastic syndromes/acute myeloid leukemia (fMDS/AML) have been reported, the epidemiology and clinical features has been poorly understood. To explore the epidemiology of this entity, we performed a retrospective nationwide epidemiological survey in Japan using questionnaire sheets. The questionnaire was sent to 561 institutions or hospitals certified by Japanese Society of Hematology, unearthing the existence of 41 pedigrees of fMDS/AML.

Genetic basis for iMCD-TAFRO.

TAFRO syndrome, a clinical subtype of idiopathic multicentric Castleman disease (iMCD), consists of a constellation of symptoms/signs including thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. The etiology of iMCD-TAFRO and the basis for cytokine hypersecretion commonly seen in iMCD-TAFRO patients has not been elucidated. Here, we identified a somatic MEK2 mutation and a germline RUNX1 mutation in two patients with iMCD-TAFRO, respectively.

Spliceosomal disruption of the non-canonical BAF complex in cancer.

SF3B1 is the most commonly mutated RNA splicing factor in cancer, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L.

Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis.

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing.

Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis.

Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy .