PUBLICATIONS

Nature Communications

Abstract The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3AINS) in AML, we here investigate the common characteristics of DNMT3AINS AML methylomes through computational analyses. We present that methylomes of DNMT3AINS AMLs are considerably different from those of DNMT3AR882 AMLs in that they exhibit increased intratumor DNA methylation heterogeneity in bivalent chromatin domains. This epigenetic heterogeneity was associated with the transcriptional variability of developmental and membrane-associated factors shaping stem cell niche, and also was a predictor of the response of AML cells to hypomethylating agents, implying that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.

International Journal of Molecular Sciences

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential cure for myelodysplastic neoplasms (MDSs) and other hematologic malignancies. This study investigates post-transplantation genetic evolution and telomere dynamics in hematopoietic cells, with a focus on clonal hematopoiesis (CH). We conducted a longitudinal analysis of 21 MDS patients who underwent allo-HSCT between September 2009 and February 2015. Genetic profiles of hematopoietic cells from both recipients and donors were compared at equivalent pre- and post-transplantation time points. Targeted sequencing identified CH-associated mutations, and real-time quantitative PCR measured telomere length. Furthermore, we compared CH incidence between recipients and age-matched controls from the GENIE cohort from routine health checkups. Post-allo-HSCT, 38% of recipients developed somatic mutations not detected before transplantation, indicating de novo CH originating from donor cells. Compared to age-matched healthy controls, recipients showed a significantly higher incidence of CH, suggesting increased susceptibility to genetic changes post-transplant. Telomere length analysis also revealed accelerated shortening in transplanted cells, highlighting the heightened stress and proliferation demands in the new microenvironment. Our findings reveal a notable incidence of donor-derived CH in allo-HSCT recipients, alongside significant telomere attrition. This suggests the potential influence of the marrow microenvironment on genetic and molecular changes in hematopoietic cells. https://www.mdpi.com/1422-0067/25/19/10258

Journal of Clinical Oncology

Abstract 7066 Background: Despite advanced treatments, including chimeric antigen receptor therapy (CAR-T), a significant proportion of patients succumb to relapsed and refractory diffuse large B cell lymphoma (R/R DLBCL). In vitro experiments suggest synergism between BTK inhibitor (BTKi) and T-cell engager, we initiated a multicenter trial of poseltinib and glofitamab in combination with lenalidomide in R/R DLBCL. Methods: This is a phase II, open label, single arm study aiming to enroll 76 participants with adult R/R DLBCL patients (NCT05335018). Patients refractory to frontline therapy or those who failed more than two lines of therapies were enrolled. Previous anti-CD19 CAR-T was allowed, while previous CD20 T-cell engager was not permitted. Participants received glofitamab (In cycle 1, dose is increased weekly from 2.5mg to 10mg, and after cycle 2, 30mg is administered on Day 1), lenalidomide (20mg daily from Day 1-14), and poseltinib (40mg twice daily from Day 1-21) (GPL) every 3 weeks for a total of 12 cycles(induction). Maintenance with poseltinib and lenalidomide for 17 cycles were given to patients after induction period. The primary endpoint is overall response rate (ORR), with secondary endpoints including duration of response (DoR), complete response rate (CRR), progression free survival (PFS), overall survival (OS), and incidence of treatment related adverse events. Results: No safety signals were observed in the safety cohort (n=6, 3+3 design). As of November 2023, 37 patients (median age 71) have been treated with GPL, with a median follow up duration of 3.6 months. In prior lines of therapy, 13 patients (35.1%) received treatment more than 2, and 26 patients (70.3%) were with Ann Arbor stage III/IV and 7 patients (18.9%) were refractory to frontline treatment. Previously, 3 patients (8.1%) received CAR-T. Out of 28 evaluable patients, ORR was 89.3%, with CRR of 42.9%. Six-month OS and PFS rate were 81% and 55%. DoR at 6 months was 66%. Neutropenia (45.9%) was the most common grade(gr) 3-4. Three patients (8.1%) died of gr5. There was 1 case (2.7%) of gr3 atrial fibrillation and gr1 bleeding. No incidence of gr3 or above liver/renal toxicity were observed. Overall, 3 patients (8.1%) discontinued GPL treatment due to toxicity, and cytokine release syndrome was observed in 7 patients (18.9%) and only 2 patients (5.4%) were gr3-4. Conclusions: Interim analysis indicates that the GPL regimen is an effective and safe regimen for R/R DLBCL patients. High response rates observed support further investigation of GPL for potential synergism between T-cell engagers and BTKi. This multicenter study is actively recruiting patients and is set to complete enrollment within this year. Clinical trial information: NCT05335018.

Nature Communications

Abstract Potential synergism between Bruton’s tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142) https://www.nature.com/articles/s41467-024-47198-4

European Heart Journal

Background and Aims Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF. Methods Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The asso- ciation between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes—the composite of heart failure, ischaemic stroke, or death—according to the presence of CHIP muta- tions in AF was investigated from the UK Biobank cohort. Results The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respect- ively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multi- variable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10–1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14–1.99, P = .004) followed by per- sistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation pre- sented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05–2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E′, and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death). Conclusions CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes

European Journal of Preventive Cardiology

Aims Clonal haematopoiesis of indeterminate potential (CHIP), defined as a clonal expansion of age-related recurrent somatic mutations, has recently emerged as a novel cardiovascular risk factor. However, the precise role of CHIP in the development of atherosclerotic cardiovascular disease (ASCVD) remains unclear. Methods Among 4,300 asymptomatic Korean participants aged 40–79 years, we investigated the risk of ASCVD by CHIP and the interplay between CHIP and conventional risk factors in ASCVD development. Additionally, we assessed changes in coronary arteries based on the presence of CHIP using coronary computed tomography angiography (CCTA). Results CHIP was present in 363 participants (8.4%), and its prevalence increased with age. Commonly mutated genes were DNMT3A, TET2 and ASXL1, in order. During follow-up (median, 4.7 years), 18 ASCVD cases (5.0%) were observed in CHIP carriers vs. 62 (1.6%) in non-carriers (p < 0.001), indicating an elevated risk of ASCVD associated with CHIP (adjusted HR 2.49, 95% CI 1.45–4.29, p < 0.001). Notably, with high levels of low-density lipoprotein (LDL) cholesterol, CHIP enhanced the risk of ASCVD (adjusted HR 6.20, 95% CI 3.14–12.23, p < 0.001), demonstrating synergism between CHIP and LDL cholesterol levels (S-index, 4.94; 95% CI 1.08–22.53, p = 0.039). Serial CCTAs confirmed that CHIP, in conjunction with high LDL cholesterol levels, had significant early impact on coronary arteries, revealing new measurable coronary atherosclerosis, mainly with unstable plaque, in proximal lesions. Conclusions The presence of CHIP was significantly associated with the risk of ASCVD, promoting the early stage of atherosclerosis through synergy with high LDL cholesterol in the general population.

Genome Medicine

Background Clonal hematopoiesis (CH) frequently progresses after chemotherapy or radiotherapy. We evaluated the clinical impact of preoperative CH on the survival outcomes of patients with non-small cell lung cancer (NSCLC) who underwent surgical resection followed by adjuvant therapy. Methods A total of 415 consecutive patients with NSCLC who underwent surgery followed by adjuvant therapy from 2011 to 2017 were analyzed. CH status was evaluated using targeted deep sequencing of blood samples collected before surgery. To minimize the possible selection bias between the two groups according to CH status, a propensity score matching (PSM) was adopted. Early-stage patients were further analyzed with additional matched cohort of patients who did not receive adjuvant therapy. Results CH was detected in 21% (86/415) of patients with NSCLC before adjuvant therapy. Patients with CH mutations had worse overall survival (OS) than those without (hazard ratio [95% confidence interval] = 1.56 [1.07–2.28], p = 0.020), which remained significant after the multivariable analysis (1.58 [1.08–2.32], p = 0.019). Of note, the presence of CH was associated with non–cancer mortality (p = 0.042) and mortality of unknown origin (p = 0.018). In patients with stage IIB NSCLC, there was a significant interaction on OS between CH and adjuvant therapy after the adjustment with several cofactors through the multivariable analysis (HR 1.19, 95% CI 1.00–1.1.41, p = 0.041). Conclusions In resected NSCLC, existence of preoperative CH might amplify CH-related adverse outcomes through adjuvant treatments, resulting in poor survival results.

EHA 2023

Background:Despite the groundbreaking introduction of rituximab for the treatment of diffuse large B cell lymphoma (DLBCL),approximately 30% of the patients ultimately experience refractory / relapse (R/R) disease and so far myriads attempts to improve survival outcomes have not yielded firm positive results. Glofitamab is a T-cell engaging bispecific antibody with a novel 2:1 configuration conferring bivalency for CD20 and monovalency for CD3 that is both effective and tolerable in patients with R/R B-cell lymphomas. On the otherhand, it is a well-known fact that the lenalidomide plus BTK inhibitor combination has a synthetic lethality against DLBCL. One of the major advantage of such combination is the absence of cytotoxic agents that may lead tounmanageable toxicities and dose limitations. Aims:We planned to test the efficacy and safety of glofitamab in combination with lenalidomide and poseltinib. Methods:This is an open-label single arm phase II study with intent to recruit 76 participants (ClinicalTrials.gov Identifier:NCT05335018). CD20 positive DLBCL (DLBCL NOS, HGBCL, trFL) patients older than 19 years of age with historyof exposure to anti-CD20 agents are deemed eligible for screening. Major exclusion criteria include (1) BCL6(-) andMYC(+) disease; (2) previous exposure to glofitamab; (3) 4 or more lines of prior therapies.The treatment schedules and durations are shown in Figure. To mitigate the risk of glofitamab associated cytokinerelease syndrome, obinutuzumab premedication and cycle 1 step-up dosing was implemented. From cycle 2, glofitama b 30mg is given on day 1 of each cycle. Lenalidomide 20mg is given daily from day 1-14 of each cycle.Poseltinib 40mg is given twice daily from day 1-21 of each cycle. Each cycle is 28 days. The primary endpoint is overall response rate. The secondary endpoints include duration of response, complete response rate, progression free survival, overall survival and treatment related adverse events. Results:Herein, we report the initial safety and efficacy data of the first 6 patients in the safety cohort (Table). The mediantime from first diagnosis to study enrollment was 25 months, with median of 2 prior lines of therapy (range 1-3).There was 1 event of cytokine release syndrome grade 1, which resolved without sequalae. The most commonadverse event was skin rash (2 grade 2, 1 grade 1) which did not require study drug modifications. Neutropeniaoccurred in 2 patients, but no dose adjustment was necessary. One patient with a previous history of priorCOVID19 infection after TNB-486 (CD19/CD3 bispecific) clinical trial, despite receiving vaccination prior to thisstudy enrollment, experienced COVID19 reactivation after cycle 1. Glofitamab D8 and D15 doses were skipped,and both lenalidomide and posetinib were stopped for 14 days. The patient recovered and underwent full doses ofsubsequent therapies. After DSMB clearance, we are now enrolling patients in the expansion phase.For tumor response, all 6 patients achieved objective response per Lugano criteria at the end of cycle 2 (3 CR, 3PR). Based on the best overall response, there were 4 confirmed CR and the median duration of response 4 months (Table).Summary/Conclusion: Glofitamab, poseltinib and lenalidomide (GPL) is promising combination for the treatment of R/R DLBCL

Atherosclerosis

Abstract Background and aims: Studies have demonstrated that the risk of atherosclerotic cardiovascular disease (ASCVD) can be assessed by polygenic risk score (PRS) using common genetic variants. Because metabolic syndrome is a well-known, robust risk factor of ASCVD, we established PRS of metabolic disease and analyzed whether this PRS could predict incident ASCVD. Methods: We constructed PRSs for eight quantifiable metabolic phenotypes-systolic/diastolic blood pressure, body mass index (BMI), four blood lipid components, and fasting blood glucose-by genome-wide association studies of two prospective Korean cohorts (n = 37,285). We conducted a grid search of combinations of metabolic PRSs to identify the most optimal weighted score for incident ASCVD (PRSMetS-ASCVD). The utility of PRSMetS-ASCVD was validated in an independent prospective cohort (n = 4333). Results: The individuals in the highest PRS quintile demonstrated a 1.4-2.0-fold increased risk of incident hypertension, obesity, hyperlipidemia, and diabetes. Using the PRSMetS-ASCVD, we identified 6.7% of the population as a high risk group demonstrating a 3.3-fold (95% confidence interval 1.7-6.1, p < 0.001) higher risk for incident ASCVD. The model combining the PRSMetS-ASCVD demonstrated a better performance for predicting ASCVD than that consisting of only conventional risk factors, such as age, sex, BMI, smoking, hypertension, diabetes and hyperlipidemia. The population with high PRSMetS-ASCVD minimally overlapped with that of high Framingham risk score, thus suggesting the additive independent benefits beyond the Framingham risk score, especially in younger individuals. Conclusions: The polygenic risk of metabolic disease independently predicts those at an increased risk of ASCVD, identifying those at a genetically high risk of incident ASCVD.

Genetics in Medicine

Abstract Purpose: Despite the importance of exonic copy number variations (CNVs) in human genetic diseases, reliable next-generation sequencing-based methods for detecting them are unavailable. We developed an expandable and robust exonic CNV detection tool called consistent count region (CCR)-CNV. Methods: In total, about 1000 samples of the truth set were used for validating CCR-CNV. We compared CCR-CNV performance with 2 well-known CNV tools. Finally, to overcome the limitations of CCR-CNV, we devised a combined approach. Results: The mean sensitivity and specificity of CCR-CNV alone were above 95%, which was superior to that of other CNV tools, such as DECoN and Atlas-CNV. However, low covered region and positive predictive value and high false discovery rate act as obstacles to its use in clinical settings. The combined approach showed much improved performance than CCR-CNV alone. Conclusion: In this study, we present a novel diagnostic tool that allows the identification of exonic CNVs with high confidence using various reagents and clinical next-generation sequencing platforms. We validated this method using the largest multiple ligation-dependent probe amplification-confirmed data set, including sufficient copy normal control data. The approach, combined with existing CNV tools, allows the implementation of CCR-CNV in clinical settings. Keywords: Copy number variation; Germline; Molecular genetics; Targeted gene panel clinical sequencing. https://linkinghub.elsevier.com/retrieve/pii/S1098-3600(21)05377-6

Nature Communications

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

European Journal of Human Genetics

Direct haplotyping enables noninvasive prenatal testing (NIPT) without analyzing proband, which is a promising strategy for pregnancies at risk of an inherited single-gene disorder. Here, we aimed to expand the scope of single-gene disorders that NIPT using linked-read direct haplotyping would be applicable to. Three families at risk of myotonic dystrophy type 1, lipoid congenital adrenal hyperplasia, and Fukuyama congenital muscular dystrophy were recruited. All cases exhibited distinct characteristics that are often encountered as hurdles (i.e., repeat expansion, identical variants in both parents, and novel variants with retrotransposon insertion) in the universal clinical application of NIPT. Direct haplotyping of parental genomes was performed by linked-read sequencing, combined with allele-specific PCR, if necessary. Target DMPK, STAR, and FKTN genes in the maternal plasma DNA were sequenced. Posterior risk calculations and an Anderson–Darling test were performed to deduce the maternal and paternal inheritance, respectively. In all cases, we could predict the inheritance of maternal mutant allele with > 99.9% confidence, while paternal mutant alleles were not predicted to be inherited. Our study indicates that direct haplotyping and posterior risk calculation can be applied with subtle modifications to NIPT for the detection of an expanded range of diseases.

Thromosis Research

Considering difficulties in on-site ADAMTS13 testing and the performance instability of PLASMIC score according to ethnicity, we developed a prediction tool, MED-TMA (machine learning (ML) method for differential diagnosis (DDx) of thrombotic microangiopathy (TMA)) to support clinical decision. Data from 319 patients visiting 31 hospitals in Korea clinically diagnosed with primary TMA was randomly separated by 2:1 into two groups – the development dataset (D-set, n = 212), the validation dataset (V-set, n = 107). Feature elimination was conducted to select optimal clinical predictors. We developed the model with the selected features using ML methods, verifying using V-set. After the feature elimination using 19 clinical variables, five variables were selected with high importance value. Among nine ML methods, four ML methods were chosen considering the Area Under the Curves (AUC) and the correlation between the methods using D-set. We developed MED-TMA based on an optimized ensemble model with the selected four ML methods resulting in AUC values of 0.945 and 0.924 in D-set and V-set, respectively. In addition to the binary outcome, MED-TMA was capable of providing a probability for DDx of TMA. The ensemble approach driven MED-TMA showed comparable accurate and intuitive decision support for DDx of TMA to that of the existing models based on a single ML method. We provide a web-based nomogram for the appropriate use of effective but costly therapeutics to treat TMA patients (http://hematology.snu.ac.kr/medtma/).

BMC Cancer

Background: Trichilemmal carcinoma (TC) is an extremely rare hair follicle tumor. We aimed to explore the genetic abnormalities involved in TC to gain insight into its molecular pathogenesis.Methods: Data from patients diagnosed with TC within a 12-year period were retrospectively reviewed. Genomic DNA isolated from a formalin-fixed paraffin-embedded (FFPE) tumor tissue block was sequenced and explored for a panel of cancer genes. Results: DNA was extracted from the FFPE tissue of four patients (50% female; mean age, 51.5 years) diagnosed with TC for analysis. The tumor was located in the head and neck of three patients and in the shoulder of one patient. TP53 mutations (p.Arg213, p.Arg249Trp, and p.Arg248Gln) were found in three patients. Fusions previously identified in melanoma were detected in two patients (TACC3-FGFR3 and ROS1-GOPC fusions). Other mutations found included NF1-truncating mutation (Arg1362), NRAS mutation (p.Gln61Lys), TOP1 amplification, and PTEN deletion. Overall, genetic changes found in TC resemble that of other skin cancers, suggesting similar pathogenesis. All patients with TP53 mutations had aggressive clinical course, two who died (OS 93 and 36 months), and one who experienced recurrent relapse. Conclusions: We reported the genomic variations found in TC, which may give insight into the molecular pathogenesis. Overall, genetic changes found in TC resembled that of other skin cancers, suggesting similar pathogenesis. TP53 mutations was were identified in patients who had an aggressive clinical course. Genetic alterations identified may further suggest the potential treatment options of TC. Keywords: Trichilemmal carcinoma, DNA sequencing, Molecular pathogenesis

Clinical Chemistry

Reconstruction of parental haplotypes is a major step in noninvasive prenatal testing (NIPT) for singlegene disorders (1). Indirect haplotyping, based on genotypes of the mother, father, and proband, is challenging when the genotype of the proband is unavailable (2). A 2017 study by Hui et al. made a progress in NIPT for single-gene disorders through direct haplotyping using linked-read sequencing (10 X genomics), thereby resolving the drawback of indirect haplotyping (3). This method has been applied successfully to several monogenic disorders such as congenital adrenal hyperplasia and hemophilia (3). However, this approach warrants further examination to establish its clinical applicability to a range of single-gene disorders.

BMC Cancer

Background: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets. Methods: Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines. Results: WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNASeq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells. Conclusions: We propose that NPM1 is a novel therapeutic target for AT/RTs. Keywords: Atypical teratoid/rhabdoid tumor, NPM1, Nucleophosmin

Blood Cancer Journal

Myeloid sarcoma (MS), or granulocytic sarcoma, is a rare extramedullary tumor of immature myeloid cells. MS may present simultaneously with or during the course of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or any forms of myeloproliferative neoplasms (MPN). Less commonly, it is detected as an isolated form without bone marrow (BM) involvement. Although the prognosis of MS has not been well examined due to the rarity of this disorder, it is known to be refractory to standard therapies of AML and is generally associated with a poor outcome1. Furthermore, it has been noted that patients with myeloid sarcoma have a predisposition to extramedullary relapses.