Comprehensive microRNA analyses using vitreous humor of ocular sarcoidosis.

PURPOSE: MicroRNAs (miRNAs) are non-coding RNAs which have attracted attention as biomarkers in a variety of diseases. However, extensive unbiased analysis of miRNA in vitreous humor of sarcoidosis patients has not been reported. In the present study, we comprehensively analyzed the dysregulated miRNAs in ocular sarcoidosis to search for potential biomarkers. MATERIALS AND METHODS: This study included seven patients diagnosed with ocular sarcoidosis (five definite and two presumed). Five patients with unclassified uveitis and 24 with non-inflammatory diseases served as controls. MicroRNA expression levels in vitreous humor samples were measured by microarray, and differentially expressed miRNAs between sarcoidosis and other diseases were explored. Next, pathway enrichment analysis was performed to evaluate the functions of the dysregulated miRNAs, and machine learning was used to search for candidate biomarkers. RESULTS: A total of 614 upregulated miRNAs and 8 downregulated miRNAs were detected in vitreous humor of patients with ocular sarcoidosis compared with patients with unclassified uveitis and non-inflammatory diseases. Some dysregulated miRNAs were involved in the TGF-ß signaling pathway. Furthermore, we identified miR-764 as the best predictor for ocular sarcoidosis using Boruta selection. CONCLUSIONS: In this study, comprehensive miRNA analysis of vitreous humor samples identified dysregulated miRNAs in ocular sarcoidosis. This study suggests new insights into molecular pathogenetic mechanisms of sarcoidosis and may provide useful information toward developing novel diagnostic biomarkers and therapeutic targets for sarcoidosis.

A single-institution retrospective study of comprehensive genomic profiling tests based on C-CAT findings for advanced solid cancers.

BACKGROUND: In recent years, as the availability of precision therapies expands, there is increasing reliance on genomic profiling assays to help identify the most appropriate treatment options for patients with advanced cancers. We retrospectively investigated the results of comprehensive genomic profiling tests from the time insurance coverage began until recently and examined the status of genetic analysis. METHODS: We retrospectively reviewed the analysis results of 300 patients with advanced solid tumors who consented to comprehensive genomic profiling tests from October 2019 to December 2022. RESULTS: Of the 300 patients who underwent comprehensive genomic profiling tests, analysis results for 274 patients were obtained, and were reviewed by the Clinical Genome Expert Panel. Six specimens (2%) were discontinued due to patient deaths and deteriorations in general condition. The three most frequently occurring actionable genomic alterations observed were TP53 (47.4%), KRAS (28.1%) and CDKN2A (20.4%). The most common druggable variant was CDKN2A, which was noted in 52 (19%) of 274 patients. The next most common were PIK3CA, BRAF, KRAS and PTEN. The cancer types that showed a greater median number of actionable alterations comprised thyroid cancer, pancreatic cancer and colorectal cancer. CONCLUSIONS: In conclusion, comprehensive genomic profiling tests have the potential to be valuable in identifying genomic abnormalities. Even if there is no effective treatment at present, it may lead to a treatment in the future. Comprehensive genomic profiling tests should be considered for any cancer.

Analysis of Carcinogenic Involvement of MicroRNA Pattern in Peripheral Non-Cancerous Tissues and Chronic Viral Liver Injury.

Risk factors for hepatocarcinogenesis include chronic inflammation due to viral infection, liver fibrosis, and aging. In this study, we separated carcinogenic and non-carcinogenic cases due to hepatitis C virus (HCV) infection, aiming to comprehensively analyze miRNA expression in liver tissues by age, and identify factors that contribute to carcinogenesis. Total RNA was extracted from 360 chronic hepatitis C (CH), 43 HCV infected hepatocellular carcinoma (HCC), and surrounding non-tumor (SNT) tissues. MicroRNA (miRNA) expression patterns were analyzed using microarray. Using machine learning, we extracted characteristic miRNA expression patterns for each disease and age. There were no age-dependent changes in miRNA expression in the disease-specific comparisons; however, miRNA expression differed among the age groups of 50, 60, and 70 years of age between CH and SNT. The expression of miRNA was different between SNT and HCC only in patients in their 70s. Of the 55 miRNAs with significant differences in expression between CH and SNT, 34 miRNAs showed significant differences in expression even in the degree of liver fibrosis. The observation that miRNAs involved in hepatocarcinogenesis differ at different ages suggests that the mechanisms of carcinogenesis differ by age group as well. We also found that many miRNAs whose expression did not affect liver fibrosis were involved in carcinogenesis. These findings are expected to define biomarkers for detection of HCC at early stage, and develop novel therapeutic targets for HCC.

Novel Artificial Intelligence Combining Convolutional Neural Network and Support Vector Machine to Predict Colorectal Cancer Prognosis and Mutational Signatures From Hematoxylin and Eosin Images.

Reducing recurrence following radical resection of colon cancer without overtreatment or undertreatment remains a challenge. Postoperative adjuvant chemotherapy (Adj) is currently administered based solely on pathologic TNM stage. However, prognosis can vary significantly among patients with the same disease stage. Therefore, novel classification systems in addition to the TNM are necessary to inform decision-making regarding postoperative treatment strategies, especially stage II and III disease, and minimize overtreatment and undertreatment with Adj. We developed a prognostic prediction system for colorectal cancer using a combined convolutional neural network and support vector machine approach to extract features from hematoxylin and eosin staining images. We combined the TNM and our artificial intelligence (AI)-based classification system into a modified TNM-AI classification system with high discriminative power for recurrence-free survival. Furthermore, the cancer cell population recognized by this system as low risk of recurrence exhibited the mutational signature SBS87 as a genetic phenotype. The novel AI-based classification system developed here is expected to play an important role in prognostic prediction and personalized treatment selection in oncology.

Liver-specific DICER1 syndrome model mice develop cystic liver tumors with defective primary cilia.

DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland.

Plasma extracellular vesicle microRNAs reflecting the therapeutic effect of the CBP/ß-catenin inhibitor PRI-724 in patients with liver cirrhosis.

There is an unmet need for antifibrotic therapies to prevent the progression of liver cirrhosis. Previously, we conducted an exploratory trial to assess the safety and antifibrotic efficacy of PRI-724, a selective CBP/ß-catenin inhibitor, in patients with liver cirrhosis. PRI-724 was well tolerated and exerted a potential antifibrotic effect. Here, we investigated whether the profiles of circulating microRNAs packaged in extracellular vesicles (EV-miRNAs) are associated with responses to liver fibrosis treatments. Eighteen patients who received PRI-724 for 12 weeks in a phase 1/2a study were classified as responders (n = 10) or non-responders (n = 8) based on changes in liver stiffness. Plasma samples were obtained before and after PRI-724 administration and the levels of EV-miRNAs were analyzed. Three miRNAs (miR-6510-5p, miR-6772-5p, and miR-4261) were identified as predictors of response or non-response to PRI-724, and the levels of three other miRNAs (miR-939-3p, miR-887-3p, and miR-7112-5p) correlated with the efficacy of treatment. Expression of miR-887-3p was detected in hepatocytes and was decreased significantly in liver tissue following PRI-724 treatment. In addition, transfection of a miR-887-3p mimic activated hepatic stellate cells. Thus, decreases in the miR-887-3p level in blood may reflect recovery from liver fibroses in patients with liver cirrhosis treated with PRI-724, although further validation studies are warranted to confirm this.

miR­146a­5p and miR­191­5p as novel diagnostic marker candidates for ovarian clear cell carcinoma.

Ovarian cancer is a malignant gynecologic disease rarely diagnosed in the early stages. Among the various types of ovarian cancer, clear cell carcinoma has a poor prognosis due to its malignant potential. MicroRNAs (miRNAs/miRs) regulate gene expression in cells by suppressing the translation of target genes or by degrading the target mRNA. miRNAs are also secreted from the cells in the blood, binding to proteins or lipids and assisting in cell-cell communication. Therefore, serum miRNAs may be considered potential diagnostic biomarkers for ovarian cancer. The present study investigated and identified specific miRNAs associated with ovarian clear cell carcinoma and compared them to those in ovarian endometrioma samples and healthy controls. CA125, an ovarian tumor marker, did not differ between patients with ovarian clear cell carcinoma, endometriosis or healthy controls. Subsequently, four miRNAs (miR-146a-5p, miR-191-5p, miR-484 and miR-574-3p) were analyzed. The expression levels of miR-146a-5p and miR-191-5p were significantly increased in the serum samples from patients with ovarian clear cell carcinoma compared with those in the healthy controls, but there was no significant difference compared with in patients with endometriosis. Furthermore, the bioinformatics analysis showed that CCND2 and NOTCH2 were the candidate target genes of miR-146a-5p and miR-191-5p. In conclusion, the results of the present study demonstrated that miR-146a-5p and miR-191-5p may be useful as early and non-invasive diagnostic tools in ovarian clear cell carcinoma. These miRNAs can help in distinguishing between ovarian clear cell carcinoma and ovarian endometrioma. To the best of our knowledge, no previous studies have screened any candidates specifically for ovarian clear cell carcinoma.

Characterization of circulating miRNAs in the treatment of primary liver tumors.

BACKGROUND AND AIM: Circulating micro RNAs (miRNAs) indicate clinical pathologies such as inflammation and carcinogenesis. In this study, we aimed to investigate whether miRNA expression level patterns in could be used to diagnose hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), and the relationship miRNA expression patterns and cancer etiology. METHODS: Patients with HCC and BTC with indications for surgery were selected for the study. Total RNA was extracted from the extracellular vesicle (EV)-rich fraction of the serum and analyzed using Toray miRNA microarray. Samples were divided into two cohorts in order of collection, the first 85 HCC were analyzed using a microarray based on miRBase ver.2.0 (hereafter v20 cohort), and the second 177 HCC and 43 BTC were analyzed using a microarray based on miRBase ver.21 (hereafter v21 cohort). RESULTS: Using miRNA expression patterns, we found that HCC and BTC could be identified with an area under curve (AUC) 0.754 (v21 cohort). Patients with anti-hepatitis C virus (HCV) treatment (SVR-HCC) and without antiviral treatment (HCV-HCC) could be distinguished by an AUC 0.811 (v20 cohort) and AUC 0.798 (v21 cohort), respectively. CONCLUSIONS: In this study, we could diagnose primary hepatic malignant tumor using miRNA expression patterns. Moreover, the difference of miRNA expression in SVR-HCC and HCV-HCC can be important information for enclosing cases that are prone to carcinogenesis after being cured with antiviral agents, but also for uncovering the mechanism for some carcinogenic potential remains even after persistent virus infection has disappeared.

Potent antitumor effects of the conditioned medium of bone marrow-derived mesenchymal stem cells via IGFBP-4.

Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive molecules, cell-free therapy using the conditioned medium (CM) of MSCs is an attractive option. However, the effects of MSC-CM on tumor progression have not been fully elucidated. Herein, we addressed this issue and investigated the possible underlying molecular mechanisms. The CM of MSCs derived from human bone marrow greatly inhibited the in vitro growth of several human tumor cell lines and the in vivo growth of the SCCVII murine squamous cell carcinoma cell line with reduced neovascularization. Exosomes in the MSC-CM were only partially involved in the inhibitory effects. The CM contained a variety of cytokines including insulin-like growth factor binding proteins (IGFBPs). Among them, IGFBP-4 greatly inhibited the in vitro growth of these tumors and angiogenesis, and immunodepletion of IGFBP-4 from the CM significantly reversed these effects. Of note, the CM greatly reduced the phosphorylation of AKT, ERK, IGF-1 receptor beta, and p38 MAPK in a partly IGFBP4-dependent manner, possibly through its binding to IGF-1/2 and blocking the signaling. The CM depleted of IGFBP-4 also reversed the inhibitory effects on in vivo tumor growth and neovascularization. Thus, MSC-CM has potent inhibitory effects on tumor growth and neovascularization in an IGFBP4-dependent manner, suggesting that cell-free therapy using MSC-CM could be a safer promising alternative for even cancer patients.

Optimal DNA quality preservation process for comprehensive genomic testing of pediatric clinical autopsy formalin-fixed, paraffin-embedded tissues.

Clinical autopsies are performed to reveal the process of the disease that caused patient death and validate the diagnosis and treatment decisions. In pediatric clinical autopsy, the feedback provided to bereaved families has a considerable social impact; however, pediatric diseases are diverse, which makes it difficult to elucidate them. Therefore, it is necessary to employ molecular biology techniques in addition to conventional methods. Formalin-fixed, paraffin-embedded (FFPE) tissues are routinely prepared. However, clinical autopsy FFPE tissue processing is not standardized, and it is unclear whether DNA from such tissues can be used for comprehensive genomic analysis. In this study, we evaluated the DNA quality of FFPE tissues from 15 recent autopsy cases at a single-center children's hospital using quantitative polymerase chain reaction [PCR (Q129/Q41)] and nanoelectrophoresis (DNA integrity number (DIN)). Good quality DNA was obtained from every organ type excluding bone marrow within 6 days of formalin fixation. Prolonged proteinase K digestion (48 h > 24 h > 1 h) and thicker tissue sections (10 µm > 1 µm) improved Q129/Q41; however, 24 h fixed FFPE tissues showed better DNA quality. We propose an optimal and feasible workflow for storing short-term fixed FFPE tissues as DNA-preserved FFPE tissues for future comprehensive genomic searches.

Acerola exosome-like nanovesicles to systemically deliver nucleic acid medicine via oral administration.

Extracellular vesicles derived from mammalian cells could be useful carriers for drug delivery systems (DDSs); however, with regard to clinical application, there are several issues to be overcome. Acerola (Malpighia emarginata DC.) is a popular health food. In this study, the feasibility of orally administered nucleic acid drug delivery by acerola exosome-like nanoparticles (AELNs) was examined. AELNs were recovered from acerola juice using an affinity column instead of ultracentrifugation. MicroRNA (miRNA) was sufficiently encapsulated in AELNs by 30-min incubation on ice and was protected against RNase, strong acid, and base treatments. The administration of an AELN/miRNA mixture in cells achieved downregulation of the miRNA's target gene, and this mixture showed cytoplasmic localization. AELNs orally delivered small RNA to the digestive system in vivo. The target gene-suppressing effect in the small intestine and liver peaked 1 day after administration, indicating potential for use as an oral DDS for nucleic acid in the digestive system.

Comprehensive analysis of liver and blood miRNA in precancerous conditions.

Streptozotocin administration to mice (STZ-mice) induces type I diabetes and hepatocellular carcinoma (HCC). We attempted to elucidate the carcinogenic mechanism and the miRNA expression status in the liver and blood during the precancerous state. Serum and liver tissues were collected from STZ-mice and non-treated mice (CTL-mice) at 6, 10, and 12 W. The exosome enriched fraction extracted from serum was used. Hepatic histological examination and hepatic and exosomal miRNA expression analysis were serially performed using next-generation sequencing (NGS). Human miRNA expression analysis of chronic hepatitis liver tissue and exosomes, which were collected before starting the antiviral treatment, were also performed. No inflammation or fibrosis was found in the liver of CTL-mice during the observation period. In STZ-mice, regeneration and inflammation of hepatocytes was found at 6 W and nodules of atypical hepatocytes were found at 10 and 12 W. In the liver tissue, during 6-12 W, the expression levels of let-7f-5p, miR-143-3p, 148a-3p, 191-5p, 192-5p, 21a-5p, 22-3p, 26a-5p, and 92a-3p was significantly increased in STZ-mice, and anti-oncogenes of their target gene candidates were down-regulated. miR-122-5p was also significantly down-regulated in STZ-mice. Fifteen exosomal miRNAs were upregulated in STZ-mice. Six miRNAs (let-7f-5p, miR-10b-5p, 143-3p, 191-5p, 21a-5p, and 26a-5p) were upregulated, similarly to human HCC cases. From the precancerous state, aberrant expression of hepatic miRNAs has already occurred, and then, it can promote carcinogenesis. In exosomes, the expression pattern of common miRNAs between mice and humans before carcinogenesis was observed and can be expected to be developed as a cancer predictive marker.

Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing.

High-throughput RNA sequencing (RNA-seq) uses massive parallel sequencing technology, allowing the unbiased analysis of genome-wide transcription levels and tumor mutation status. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory disease characterized by the enlargement of the ocular adnexal tissues. We analyzed RNA expression levels via RNA-seq in the biopsy specimens of three patients diagnosed with IgG4-ROD. Mucosa-associated lymphoid tissue (MALT) lymphoma, reactive lymphoid hyperplasia (RLH), normal lacrimal gland tissue, and adjacent adipose tissue were used as the controls (n = 3 each). RNA-seq was performed using the NextSeq 500 system, and genes with |fold change| ≥ 2 and p < 0.05 relative to the controls were defined as differentially expressed genes (DEGs) in IgG4-ROD. To validate the results of RNA-seq, real-time polymerase chain reaction (PCR) was performed in 30 IgG4-ROD and 30 orbital MALT lymphoma tissue samples. RNA-seq identified 35 up-regulated genes, including matrix metallopeptidase 12 (MMP12) and secreted phosphoprotein 1 (SPP1), in IgG4-ROD tissues when compared to all the controls. Many pathways related to the immune system were included when compared to all the controls. Expressions of MMP12 and SPP1 in IgG4-ROD tissues were confirmed by real-time PCR and immunohistochemistry. In conclusion, we identified novel DEGs, including those associated with extracellular matrix degradation, fibrosis, and inflammation, in IgG4-ROD biopsy specimens. These data provide new insights into molecular pathogenetic mechanisms and may contribute to the development of new biomarkers for diagnosis and molecular targeted drugs.

Effect of the extracellular component of bone marrow mesenchymal stromal cells from healthy donors on hematologic neoplasms and their angiogenesis.

Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors are a promising source of cell therapy. However, their effectiveness in cancer remains less known. This study is the first to evaluate the quality of BM-MSCs obtained from young and elderly healthy volunteers (KNT cells). The KNT cells had normal karyotypes and were positive for MSC markers (CD90, CD73, CD105). When cultured under appropriate conditions, they showed adipogenic or osteogenic potential. Hence, the anti-neoplastic effects of secretory factors [supernatant or extracellular vesicles (EV)] from KNT cells were verified using several neoplastic cells (three multiple myeloma, three myeloid leukemia, and three lymphoma cell lines). The conditioned medium (CM), but not EV, of KNT cells derived from young healthy donors significantly inhibited myeloma and lymphoma cell proliferation, but enhanced myeloid leukemia proliferation. Anti-angiogenesis effect of CM and EV derived from young KNT against hematologic neoplasia-induced angiogenesis was evident and more prominent in CM than in EV but not evident in elderly KNT-derived EV. These findings indicate that the anti-tumor effect of KNT cells depends on the types of hematologic neoplasia, with elements existing in the supernatant and not in EVs. Therefore, BM-MSC may produce soluble factors that affect cell proliferation of neoplasia, causing cell-to-cell communication. The anti-angiogenesis effect of KNT cells depends on the age of BM-MSC donors.

Downregulation of extracellular vesicle microRNA-101 derived from bone marrow mesenchymal stromal cells in myelodysplastic syndrome with disease progression.

To evaluate the mechanism underlying the communication between myeloid malignant and bone marrow (BM) microenvironment cells in disease progression, the current study established BM mesenchymal stromal cells (MSCs) and assessed extracellular vesicle (EV) microRNA (miR) expression in 22 patients with myelodysplastic syndrome (MDS) and 7 patients with acute myeloid leukemia and myelodysplasia-related changes (AML/MRC). Patients with MDS were separated into two categories based on the revised International Prognostic Scoring System (IPSS-R), and EV-miR expression in BM-MSCs was evaluated using a TaqMan low-density array. The selected miRs were evaluated using reverse transcription-quantitative PCR. The current study demonstrated that the expression of BM-MSC-derived EV-miR was heterogenous and based on MDS severity, the expression of EV-miR-101 was lower in high-risk group and patients with AML/MRC compared with the control and low-risk groups. This reversibly correlated with BM blast percentage, with which the cellular miR-101 from BM-MSCs or serum EV-miR-101 expression exhibited no association. Database analyses indicated that miR-101 negatively regulated cell proliferation and epigenetic gene expression. The downregulation of BM-MSC-derived EV-miR-101 may be associated with cell-to-cell communication and may accelerate the malignant process in MDS cells.

Induction of multiple myeloma bone marrow stromal cell apoptosis by inhibiting extracellular vesicle miR-10a secretion.

Bone marrow stromal cells (BMSCs) interact with multiple myeloma (MM) cells in the bone marrow and create a permissive microenvironment for MM cell proliferation and survival. In this study, we investigated the role of extracellular vesicles (EVs) from BMSCs derived from patients with MM (MM-BMSCs). EV-encapsulated miR-10a expression was high while intracellular miR-10a was low in MM-BMSCs. We therefore hypothesized that miR-10a was packaged into EVs that were actively released into the extracellular space. Inhibition of EV release resulted in accumulation of intracellular miR-10a, inhibition of cell proliferation, and induction of apoptosis in MM-BMSCs. In contrast, proliferation and apoptosis of BMSCs derived from healthy individuals were unaffected by inhibition of EV release. Furthermore, miR-10a derived from MM-BMSCs was transferred into MM cells via EVs and enhanced their proliferation. These results suggest that inhibition of EV release induced apoptosis in MM-BMSCs and inhibited MM cell proliferation, indicating a possible role for MM-BMSC-targeted therapy.

Author Correction: Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A novel non-invasive monitoring assay of 5-azacitidine efficacy using global DNA methylation of peripheral blood in myelodysplastic syndrome.

Purpose: Monitoring response and resistance to 5-azacitidine (AZA) is essential when treating patients with myelodysplastic syndrome (MDS). To quantify methylated DNA not only in the promoter region but also in the gene body, we established a single-molecule methylation assay (SMMA). Patients and methods: We first investigated the methylation extent (expressed as methylation index [MI]) by SMMA among 28 MDS and 6 post-MDS acute myeloid leukemia patients. We then analyzed the MI in 13 AZA-treated patients. Results: Whole-blood DNA from all 34 patients had low MI values compared with healthy volunteers (P<0.0001). DNA hypomethylation in MDS patients was more evident in neutrophils (P=0.0008) than in peripheral mononuclear cells (P=0.0713). No consistent pattern of genome-wide DNA hypomethylation was found among MDS subtypes or revised International Prognostic Scoring System (IPSS-R) categories; however, we found that the MI was significantly increased for patients at very high risk who were separated by the new cytogenetic scoring system for IPSS-R (P=0.0398). There was no significant difference in MI before AZA, regardless of the response to AZA (P=0.8689); however, sequential measurement of MI in peripheral blood demonstrated that AZA non-responders did not have normalized MI at the time of next course of AZA (P=0.0352). Conclusion: Our results suggest that sequential SMMA of peripheral blood after AZA may represent a non-invasive monitoring marker for AZA efficacy in MDS patients.

Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.