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1.
Nature ; 574(7778): 432-436, 2019 10.
Article in English | MEDLINE | ID: mdl-31597964

ABSTRACT

SF3B1 is the most commonly mutated RNA splicing factor in cancer1-4, 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 GLTSCR1L5-7. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.


Subject(s)
Chromosomal Proteins, Non-Histone/metabolism , Neoplasms/genetics , RNA Splicing , Spliceosomes/metabolism , Animals , Cell Line, Tumor , Chromatin Assembly and Disassembly/genetics , Chromosomal Proteins, Non-Histone/genetics , Humans , Mice , Neoplasm Transplantation , Neoplasms/pathology , Phosphoproteins/metabolism , RNA Splicing Factors/metabolism , Spliceosomes/genetics , Transcription Factors/metabolism
2.
Nature ; 574(7777): 273-277, 2019 10.
Article in English | MEDLINE | ID: mdl-31578525

ABSTRACT

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 leukaemia1,2. 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. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.


Subject(s)
Alternative Splicing/genetics , Carcinogenesis/genetics , Epigenesis, Genetic , Leukemia, Myeloid, Acute/genetics , Animals , Cell Line, Tumor , Cell Proliferation , DNA Methylation , DNA-Binding Proteins/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Isocitrate Dehydrogenase/genetics , Male , Mutation/genetics , RNA Polymerase II/metabolism , Serine-Arginine Splicing Factors/genetics , Transcriptome
3.
Blood ; 140(8): 875-888, 2022 08 25.
Article in English | MEDLINE | ID: mdl-35709354

ABSTRACT

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).


Subject(s)
Leukemia, Myeloid, Acute , Proto-Oncogenes , Animals , Chromosome Inversion , Chromosomes, Human, Pair 3/metabolism , DNA-Binding Proteins/metabolism , Humans , Leukemia, Myeloid, Acute/pathology , MDS1 and EVI1 Complex Locus Protein/genetics , Mice , Proto-Oncogenes/genetics , Transcription Factors/metabolism
4.
Genes Dev ; 30(9): 989-1001, 2016 05 01.
Article in English | MEDLINE | ID: mdl-27151974

ABSTRACT

Genomic analyses of the myeloid malignancies and clonal disorders of hematopoiesis that may give rise to these disorders have identified that mutations in genes encoding core spliceosomal proteins and accessory regulatory splicing factors are among the most common targets of somatic mutations. These spliceosomal mutations often occur in a mutually exclusive manner with one another and, in aggregate, account for the most frequent class of mutations in patients with myelodysplastic syndromes (MDSs) in particular. Although substantial progress has been made in understanding the effects of several of these mutations on splicing and splice site recognition, functional connections linking the mechanistic changes in splicing induced by these mutations to the phenotypic consequences of clonal and aberrant hematopoiesis are not yet well defined. This review describes our current understanding of the mechanistic and biological effects of spliceosomal gene mutations in MDSs as well as the regulation of splicing throughout normal hematopoiesis.


Subject(s)
Hematopoiesis/genetics , Myelodysplastic Syndromes/genetics , Spliceosomes/genetics , Animals , Epigenesis, Genetic , Humans , Models, Animal , Mutation/genetics , RNA Splicing
5.
Reprod Med Biol ; 22(1): e12553, 2023.
Article in English | MEDLINE | ID: mdl-38076206

ABSTRACT

Purpose: To analyze whether response to the GnRH test is a predictor of empty follicle syndrome (EFS) and to analyze independent risk factors for EFS. Methods: The GnRH test results of 3765 patients from 2016 to 2018 were used to define the reference range of the GnRH test. Risk factors for EFS were estimated by multivariate logistic analysis of 5282 cycles (5247 oocyte-retrieved cycles with GnRH agonist trigger and 35 cycles of EFS) conducted from 2016 to 2019. Results: GnRH testing showed basal hormone values as follows: median LH 5.2 (95 percentile; 1.3-12.6) mIU/mL, LH 30 min 22.0 (6.8-57.1), basal FSH 7.3 (3.0-20.5), FSH 30 min 11.5 (5.1-30.4) and FSH/LH ratio 1.5 (0.6-4.1). Independent risk factors for EFS were antral follicle count (adjusted odds ratio; 0.94, 95% CI; 0.89-0.99), basal LH (0.78, 0.66-0.90), and days duration of ovarian stimulation (1.41, 1.21-1. 60). The respective thresholds were 8 for AFC, 5.0 for basal LH, and 16 days for duration. Conclusions: LH 30 min values of the GnRH test did not predict EFS. Independent risk factors for EFS were AFC, basal LH and days duration of ovarian stimulation.

6.
Rinsho Ketsueki ; 64(9): 875-883, 2023.
Article in Japanese | MEDLINE | ID: mdl-37793861

ABSTRACT

The process of RNA splicing plays a pivotal role in gene expression and genetic information modification by converting pre-mRNA into mature mRNA. Dysregulation of this process has been associated with aberrant gene expression and function, leading to hematopoietic malignancies. Through recent clinical and mouse model analyses, insights have been gained into the mechanisms underlying splicing factor mutations that aid in myelodysplastic syndrome and acute myeloid leukemia. These mutations affect genes that modulate diverse cellular processes, including chromatin regulation, transcription factors, proliferation signaling, and inflammation pathway. The relationship between aberrant splicing and cancer remains unclear despite progress in understanding the functional consequences of splicing factor mutations. This review focuses on the mechanisms of disease development because of splicing factor mutations and their potential mechanism-based therapeutic applications.


Subject(s)
Hematologic Neoplasms , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Animals , Mice , RNA Splicing/genetics , RNA Splicing Factors/genetics , Hematologic Neoplasms/genetics , Myelodysplastic Syndromes/therapy , Leukemia, Myeloid, Acute/genetics , Mutation
7.
Cancer Sci ; 113(9): 2934-2942, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35766428

ABSTRACT

Pre-mRNA splicing is now widely recognized as a cotranscriptional and post-transcriptional mechanism essential for regulating gene expression and modifying gene product function. Mutations in genes encoding core spliceosomal proteins and accessory regulatory splicing factors are now considered among the most recurrent genetic abnormalities in patients with cancer, particularly hematologic malignancies. These include mutations in the major (U2-type) and minor (U12-type) spliceosomes, which remove >99% and ~0.35% of introns, respectively. Growing evidence indicates that aberrant splicing of evolutionarily conserved U12-type minor introns plays a crucial role in cancer as the minor spliceosome component, ZRSR2, is subject to recurrent, leukemia-associated mutations, and intronic mutations have been shown to disrupt the splicing of minor introns. Here, we review the importance of minor intron regulation, the molecular effects of the minor (U12-type) spliceosomal mutations and cis-regulatory regions, and the development of minor intron studies for better understanding of cancer biology.


Subject(s)
Neoplasms , RNA Splicing , Humans , Introns/genetics , Mutation , Neoplasms/genetics , Neoplasms/metabolism , RNA Splicing/genetics , Spliceosomes/genetics , Spliceosomes/metabolism
8.
Blood ; 136(14): 1670-1684, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32492700

ABSTRACT

Additional sex combs-like 1 (ASXL1), an epigenetic modulator, is frequently mutated in myeloid neoplasms. Recent analyses of mutant ASXL1 conditional knockin (ASXL1-MT-KI) mice suggested that ASXL1-MT alone is insufficient for myeloid transformation. In our previous study, we used retrovirus-mediated insertional mutagenesis, which exhibited the susceptibility of ASXL1-MT-KI hematopoietic cells to transform into myeloid leukemia cells. In this screening, we identified the hematopoietically expressed homeobox (HHEX) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between ASXL1-MT and HHEX in myeloid leukemogenesis. Expression of HHEX enhanced proliferation of ASXL1-MT-expressing HSPCs by inhibiting apoptosis and blocking differentiation, whereas it showed only modest effect in normal HSPCs. Moreover, ASXL1-MT and HHEX accelerated the development of RUNX1-ETO9a and FLT3-ITD leukemia. Conversely, HHEX depletion profoundly attenuated the colony-forming activity and leukemogenicity of ASXL1-MT-expressing leukemia cells. Mechanistically, we identified MYB and ETV5 as downstream targets for ASXL1-MT and HHEX by using transcriptome and chromatin immunoprecipitation-next-generation sequencing analyses. Moreover, we found that expression of ASXL1-MT enhanced the binding of HHEX to the promoter loci of MYB or ETV5 via reducing H2AK119ub. Depletion of MYB or ETV5 induced apoptosis or differentiation in ASXL1-MT-expressing leukemia cells, respectively. In addition, ectopic expression of MYB or ETV5 reversed the reduced colony-forming activity of HHEX-depleted ASXL1-MT-expressing leukemia cells. These findings indicate that the HHEX-MYB/ETV5 axis promotes myeloid transformation in ASXL1-mutated preleukemia cells.


Subject(s)
Cell Transformation, Neoplastic/genetics , Genetic Predisposition to Disease , Homeodomain Proteins/genetics , Mutation , Myeloid Cells/metabolism , Repressor Proteins/genetics , Transcription Factors/genetics , Animals , Apoptosis/genetics , Biomarkers, Tumor , Biopsy , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Cell Cycle/genetics , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Colony-Forming Units Assay , Disease Models, Animal , Gene Expression Profiling , Genetic Association Studies , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Homeodomain Proteins/metabolism , Humans , Immunophenotyping , Leukemia, Myeloid/genetics , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/mortality , Leukemia, Myeloid/pathology , Mice , Myeloid Cells/pathology , Prognosis , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Repressor Proteins/metabolism , Transcription Factors/metabolism
9.
Rinsho Ketsueki ; 61(6): 643-650, 2020.
Article in Japanese | MEDLINE | ID: mdl-32624538

ABSTRACT

Splicing factor 3b subunit 1 (SF3B1) is the most commonly mutated RNA splicing factor identified in myelodysplastic syndrome (MDS), chronic lymphocytic leukemia, and uveal melanoma. The mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here, we integrated pan-cancer RNA sequencing to identify mutant SF3B1-dependent aberrant splicing events with a positive CRISPR screen to prioritize alterations that functionally promote oncogenesis. Our results indicated that diverse, recurrent SF3B1 mutations converge on the repression of bromodomain containing 9 (BRD9), a core component of the recently described non-canonical barrier-to-autointegration factor complex (ncBAF). Mutant SF3B1 recognizes intronic sequences within BRD9 as exons, thereby permitting inclusion of aberrant sequence (i.e., poison exon) that will result in the degradation of BRD9 mRNA. BRD9 depletion results in significant loss of ncBAF at CCCTC-binding factor (CTCF)-binding loci but has no impact on the localization of canonical BAF. These actions resulted in disturbed myeloid/erythroid differentiation and promoted the development of MDS and melanoma. Of note, correcting BRD9 mis-splicing in SF3B1-mutant cells with antisense oligonucleotides (ASOs), by targeting the poison exon with CRISPR-directed mutagenesis, or via the use of spliceosomal inhibitors are all potential therapeutic options. Our results implicate disruption of ncBAF as a critical factor promoting the development of the diverse array of cancers that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.


Subject(s)
RNA Splicing , Carcinogenesis , Humans , Mutation , Phosphoproteins , RNA Splicing Factors , RNA, Messenger , Transcription Factors
10.
Reprod Med Biol ; 18(3): 290-295, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31312109

ABSTRACT

PURPOSE: The clinical utility of chlormadinone acetate tablets (Lutoral™), an orally active progestin which has been available since June 2007, was compared to an in-house vaginal suppository formulation of progesterone used between 2006 and 2007 for assisted reproductive technology (ART). METHODS: We retrospectively evaluated the efficacy and safety of chlormadinone acetate by comparing the pregnancy rates and the incidences of birth defects and hypospadias in frozen-thawed embryo transfer cycles using the in-house vaginal progesterone and those using chlormadinone acetate for luteal phase support. RESULTS: The pregnancy rates in the frozen-thawed embryo transfer cycles were 31.2% (259/831) with vaginal progesterone for luteal phase support and 31.6% (4228/13 381) with chlormadinone acetate (no significant difference). In the cycles resulting in live birth following administration of chlormadinone acetate between July 2007 and December 2015, the incidence of birth defects was 2.8% (80/2893), and the incidence of hypospadias was 0.03% (1/2893). CONCLUSIONS: These results indicate that the pregnancy rate following frozen-thawed embryo transfer using chlormadinone acetate for luteal phase support was comparable with that using vaginal progesterone, with no increased risk of birth defects, including hypospadias, which has been a concern following the use of progestins.

11.
Reprod Med Biol ; 18(3): 273-277, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31312106

ABSTRACT

PURPOSE: We evaluated the performance of anti-Müllerian hormone (AMH) measured by the Beckman Coulter fully automated Access assay to predict oocyte yield following controlled ovarian stimulation (COS) for in vitro fertilization (IVF). METHODS: The correlation between the Access assay and the pre-mixing method with Generation II ELISA assay (Gen II pre-mix assay) was assessed using 230 blood samples. The relationship of AMH level measured by the Access assay and the actual number of oocytes retrieved following COS was assessed using 3296 IVF cycles. The performances of AMH, follicle stimulating hormone (FSH), and estradiol (E2) in predicting the responses to COS were also evaluated by constructing receiver operating characteristic (ROC) curves. RESULTS: The AMH levels measured just before oocyte retrieval by the Access assay and the number of oocytes retrieved following COS showed a good correlation with R = 0.655. The ROC analysis revealed that the sensitivity of AMH was comparable with or lower than that of E2 but higher than that of FSH. CONCLUSIONS: With the improved Access AMH assays, AMH was as sensitive as E2 and could become an accurate marker of ovarian response to COS in more than 3000 Japanese IVF patients.

12.
Blood ; 123(25): 3932-42, 2014 Jun 19.
Article in English | MEDLINE | ID: mdl-24825862

ABSTRACT

High levels of HES1 expression are frequently found in BCR-ABL(+) chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however, the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-κB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, CMPs expressing BCR-ABL and Hes1 secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Blast Crisis/genetics , Gene Expression Regulation, Leukemic , Homeodomain Proteins/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Matrix Metalloproteinase 9/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Blast Crisis/metabolism , Bone Marrow Transplantation/methods , Cell Movement/genetics , Cell Proliferation , Flow Cytometry , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Homeodomain Proteins/metabolism , Humans , Kaplan-Meier Estimate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Matrix Metalloproteinase 9/metabolism , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Models, Genetic , NF-kappa B/metabolism , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Transcription Factor HES-1 , Up-Regulation
13.
Blood ; 121(17): 3434-46, 2013 Apr 25.
Article in English | MEDLINE | ID: mdl-23471304

ABSTRACT

RUNX1/AML1 mutations have been identified in myelodysplastic syndromes (MDSs). In a mouse bone marrow transplantation model, a RUNX1 mutant, D171N, was shown to collaborate with Evi1 in the development of MDSs; however, this is rare in humans. Using enforced expression in human CD34(+) cells, we showed that the D171N mutant, the most frequent target of mutation in the RUNX1 gene, had an increased self-renewal capacity, blocked differentiation, dysplasia in all 3 lineages, and tendency for immaturity, but no proliferation ability. BMI1 overexpression was observed in CD34(+) cells from the majority of MDS patients with RUNX1 mutations, but not in D171N-transduced human CD34(+) cells. Cotransduction of D171N and BMI1 demonstrated that BMI1 overexpression conferred proliferation ability to D171N-transduced cells in both human CD34(+) cells and a mouse bone marrow transplantation model. Stepwise transduction of D171N followed by BMI1 in human CD34(+) cells resulted in long-term proliferation with a retained CD34(+) cell fraction, which is quite similar to the phenotype in patients with higher-risk MDSs. Our results indicate that BMI1 overexpression is one of the second hit partner genes of RUNX1 mutations that contribute to the development of MDSs.


Subject(s)
Cell Transformation, Neoplastic/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Mutation/genetics , Myelodysplastic Syndromes/pathology , Polycomb Repressive Complex 1/metabolism , Aged , Animals , Antigens, CD34/metabolism , Blotting, Western , Bone Marrow Transplantation , Cell Differentiation , Cell Proliferation , Flow Cytometry , Humans , Male , Mice , Mice, Inbred C57BL , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Phenotype , Polycomb Repressive Complex 1/genetics , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction
14.
Ann Hematol ; 93(3): 393-401, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23975214

ABSTRACT

Lymphoma-associated hemophagocytic syndrome (LAHS) is a serious disorder, and its early diagnosis and treatment with appropriate chemotherapy are very important. However, reliable markers for early diagnosis of LAHS have not been identified. We screened serum cytokines using a newly introduced assay system, cytometric bead array (CBA), and identified interferon-inducible protein 10 (IP-10)/CXCL10 and monokine induced by interferon gamma (MIG)/CXCL9 as useful markers. Serum concentrations of IP-10 and MIG at the time of LAHS diagnosis were greater than 500 and 5,000 pg/ml, respectively. The sensitivity and specificity for LAHS diagnosis were 100 and 95 %, respectively, when we set the above values as the cut-off levels. Serum levels of these two chemokines were already elevated at the time of admission and significantly decreased after successful treatment, indicating their usefulness for both the diagnosis and therapeutic outcomes for LAHS. IP-10 and MIG were also useful in distinguishing severe from moderate/mild LAHS, and B-cell-type LAHS from T-cell/natural killer cell-type LAHS. Furthermore, IP-10 and MIG were of use to distinguish LAHS from sepsis in patients with hematologic malignancies. Rapid measurement of IP-10 and MIG by CBA appeared to be important for early diagnosis and treatment of LAHS.


Subject(s)
Biomarkers, Tumor/blood , Chemokine CXCL10/blood , Chemokine CXCL9/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphoma, Non-Hodgkin/physiopathology , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Diagnosis, Differential , Follow-Up Studies , Hospitals, Urban , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/prevention & control , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/pathology , Middle Aged , Neoplasm Staging , Reagent Kits, Diagnostic , Retrospective Studies , Sensitivity and Specificity , Severity of Illness Index , Young Adult
15.
Acta Haematol ; 132(1): 108-11, 2014.
Article in English | MEDLINE | ID: mdl-24525901

ABSTRACT

A 79-year-old man with a 2-month history of fever and weight loss was admitted to our hospital because of an acute abdomen. Abdominal CT scans showed marked sectional thickening and edema of the small intestine. On laparotomy, a 16-cm section of the small intestine was ischemic and necrotic; therefore, segmentectomy of the intestine was performed. A thrombus was noted at the stump of the mesenteric artery branch. Histopathological analysis of the resected intestine revealed fibrin thrombi in both mesenteric arteries and veins. Furthermore, a cluster of large, abnormal lymphoid cells bordering the intima of most branches of the mesenteric veins and small vessels was observed. Immunohistochemical analysis revealed that these abnormal cells were positive for CD20, leading to a diagnosis of intravascular large B-cell lymphoma (IVLBCL). The patient was successfully treated with standard R-CHOP chemotherapy; however, the lymphoma recurred in the central nervous system 18 months after the initial diagnosis, and the patient died. Simultaneous thrombosis of the mesenteric artery and vein is unusual as a clinical manifestation of IVLBCL. However, IVLBCL should be taken into consideration when ischemic disorders of unknown cause, accompanied by fever of unknown origin, are encountered.


Subject(s)
Lymphoma, B-Cell/diagnosis , Mesenteric Arteries/pathology , Mesenteric Veins/pathology , Thrombosis/pathology , Vascular Neoplasms/diagnosis , Aged , Fatal Outcome , Fever of Unknown Origin/etiology , Humans , Intestine, Small/blood supply , Intestine, Small/pathology , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/therapy , Male , Thrombosis/etiology , Vascular Neoplasms/pathology , Vascular Neoplasms/therapy , Venous Thrombosis/etiology , Venous Thrombosis/pathology
16.
Proc Jpn Acad Ser B Phys Biol Sci ; 90(10): 389-404, 2014.
Article in English | MEDLINE | ID: mdl-25504228

ABSTRACT

Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis.


Subject(s)
Cell Transformation, Neoplastic/genetics , Epigenesis, Genetic , Hematologic Neoplasms/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , Myelodysplastic Syndromes/genetics , Animals , Cell Proliferation/genetics , Cell Transformation, Neoplastic/metabolism , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Hematologic Neoplasms/metabolism , Humans , Leukemia, Myeloid, Acute/metabolism , Mice , Myelodysplastic Syndromes/metabolism
17.
Exp Hematol ; 132: 104173, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38309573

ABSTRACT

In the intricate orchestration of the central dogma, pre-mRNA splicing plays a crucial role in the post-transcriptional process that transforms DNA into mature mRNA. Widely acknowledged as a pivotal RNA processing step, it significantly influences gene expression and alters the functionality of gene product proteins. Although U2-dependent spliceosomes efficiently manage the removal of over 99% of introns, a distinct subset of essential genes undergo splicing with a different intron type, denoted as minor introns, using U12-dependent spliceosomes. Mutations in spliceosome component genes are now recognized as prevalent genetic abnormalities in cancer patients, especially those with hematologic malignancies. Despite the relative rarity of minor introns, genes containing them are evolutionarily conserved and play crucial roles in functions such as the RAS-MAPK pathway. Disruptions in U12-type minor intron splicing caused by mutations in snRNA or its regulatory components significantly contribute to cancer progression. Notably, recurrent mutations associated with myelodysplastic syndrome (MDS) in the minor spliceosome component ZRSR2 underscore its significance. Examination of ZRSR2-mutated MDS cells has revealed that only a subset of minor spliceosome-dependent genes, such as LZTR1, consistently exhibit missplicing. Recent technological advancements have uncovered insights into minor introns, raising inquiries beyond current understanding. This review comprehensively explores the importance of minor intron regulation, the molecular implications of minor (U12-type) spliceosomal mutations and cis-regulatory regions, and the evolutionary progress of studies on minor, aiming to provide a sophisticated understanding of their intricate role in cancer biology.


Subject(s)
Hematologic Neoplasms , Myelodysplastic Syndromes , Humans , Introns , Spliceosomes/genetics , Spliceosomes/metabolism , RNA Splicing , RNA, Messenger/genetics , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Transcription Factors/genetics
18.
Nagoya J Med Sci ; 86(2): 333-340, 2024 May.
Article in English | MEDLINE | ID: mdl-38962420

ABSTRACT

To the best of our knowledge, this is the first case of pregnancy with a healthy baby after treatment with an oral gonadotropin-releasing hormone (GnRH) antagonist in women with premature ovarian insufficiency. A 36-year-old female presented at our hospital after being diagnosed with premature ovarian insufficiency by a previous doctor. We administered clomiphene, human menopausal gonadotropin (hMG), and GnRH antagonist (injection) together with estrogen replacement for 11 cycles (27 months), but no follicular development was observed. When the oral GnRH antagonist (relugolix), which has recently become available, was used in the 12th cycle, follicular growth of 13 mm was confirmed on the 14th day of stimulation. After stimulation, the use of hMG and GnRH antagonist (injection) was continued, and a maturation trigger, human chorionic gonadotropin 10000 IU, was administered. Oocyte retrieval was performed successfully, intracytoplasmic sperm injection and frozen embryo transfer were performed, and fetal heartbeat was confirmed. The patient was admitted to the perinatal management facility. She delivered a healthy baby of 3,732 g via cesarean section at 41 weeks +2. This case shows the possibility of using an oral GnRH antagonist as an option for infertility treatment.


Subject(s)
Gonadotropin-Releasing Hormone , Primary Ovarian Insufficiency , Humans , Female , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Primary Ovarian Insufficiency/drug therapy , Adult , Pregnancy , Administration, Oral , Hormone Antagonists/therapeutic use , Hormone Antagonists/administration & dosage , Ovulation Induction/methods
19.
Int J Hematol ; 117(6): 821-829, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37041345

ABSTRACT

Hematopoiesis is maintained and regulated by a bone marrow-specific microenvironment called a niche. In hematological malignancies, tumor cells induce niche remodeling, and the reconstructed niche is closely linked to disease pathogenesis. Recent studies have suggested that extracellular vesicles (EVs) secreted from tumor cells play a principal role in niche remodeling in hematological malignancies. Although EVs are emerging as potential therapeutic targets, the underlying mechanism of action remains unclear, and selective inhibition remains a challenge. This review summarizes remodeling of the bone marrow microenvironment in hematological malignancies and its contribution to pathogenesis, as well as roles of tumor-derived EVs, and provides a perspective on future research in this field.


Subject(s)
Extracellular Vesicles , Hematologic Neoplasms , Myeloproliferative Disorders , Humans , Bone Marrow/pathology , Extracellular Vesicles/pathology , Myeloproliferative Disorders/pathology , Hematologic Neoplasms/pathology , Hematopoiesis , Tumor Microenvironment
20.
Leukemia ; 37(9): 1802-1811, 2023 09.
Article in English | MEDLINE | ID: mdl-37464069

ABSTRACT

SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1fl/fl. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.


Subject(s)
Hematopoiesis , Leukemia, Myeloid, Acute , Animals , Humans , Mice , Carrier Proteins/genetics , Cell Differentiation , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Leukemia, Myeloid, Acute/pathology , Mutation , Nuclear Proteins/genetics
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