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Multiparameter flow cytometry (MPF) is an essential component of the diagnostic workup of hematologic malignancies. Recently developed tools have expanded the utility of MPF in detecting T-cell clonality and myelomonocytic dysplasia. Minimal/measurable residual disease analysis has long been established as critical in the management of B-lymphoblastic leukemia and is emerging as a useful tool in myeloid malignancies. With the continued increased complexity of MPF assays, emerging tools for data collection and analysis will allow users to take full advantage of MPF in the diagnosis of hematologic disease.
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Citometría de Flujo , Neoplasias Hematológicas , Humanos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/patología , Inmunofenotipificación , Neoplasia Residual/diagnósticoRESUMEN
High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.5 g/m2) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010-2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2-3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3-4 thrombocytopenia in 58%. No neurotoxicity was observed. HD-MTX can be safely used with supportive care and monitoring.
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Antimetabolitos Antineoplásicos , Neoplasias del Sistema Nervioso Central , Metotrexato , Humanos , Metotrexato/efectos adversos , Metotrexato/administración & dosificación , Femenino , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Masculino , Preescolar , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Lactante , Niño , Estudios de Seguimiento , Estudios Retrospectivos , Pronóstico , Mucositis/inducido químicamente , Neutropenia/inducido químicamenteRESUMEN
INTRODUCTION: A noncoding variant (rs35349669) within INPP5D, a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well-studied in amyloid pathology, its role in tau pathology remains unclear. METHODS: PS19 Tauopathy mice were crossed with Inpp5d-haplodeficient (Inpp5d+/-) mice to examine the impact of Inpp5d in tau pathology. RESULTS: Increased INPP5D expression correlated positively withâ¯phospho-Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up-regulation of genes associatedâ¯with immune response and cell migration. DISCUSSION: Our findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient-Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits. HIGHLIGHTS: The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model. INPP5D expression is associated with tau pathology. Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho-Tau levels. Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration. These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.
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Modelos Animales de Enfermedad , Ratones Transgénicos , Tauopatías , Proteínas tau , Animales , Ratones , Encéfalo/patología , Encéfalo/metabolismo , Fosforilación , Proteínas tau/metabolismo , Tauopatías/patología , Tauopatías/metabolismo , Tauopatías/genéticaRESUMEN
Understanding microglial states in the aging brain has become crucial, especially with the discovery of numerous Alzheimer's disease (AD) risk and protective variants in genes such as INPP5D and TREM2, which are essential to microglia function in AD. Here we present a thorough examination of microglia-like cells and primary mouse microglia at the proteome and transcriptome levels to illuminate the roles these genes and the proteins they encode play in various cell states. First, we compared the proteome profiles of wildtype and INPP5D (SHIP1) knockout primary microglia. Our findings revealed significant proteome alterations only in the homozygous SHIP1 knockout, revealing its impact on the microglial proteome. Additionally, we compared the proteome and transcriptome profiles of commonly used in vitro microglia BV2 and HMC3 cells with primary mouse microglia. Our results demonstrated a substantial similarity between the proteome of BV2 and mouse primary cells, while notable differences were observed between BV2 and human HMC3. Lastly, we conducted targeted lipidomic analysis to quantify different phosphatidylinositols (PIs) species, which are direct SHIP1 targets, in the HMC3 and BV2 cells. This in-depth omics analysis of both mouse and human microglia enhances our systematic understanding of these microglia models. SIGNIFICANCE: Given the growing urgency of comprehending microglial function in the context of neurodegenerative diseases and the substantial therapeutic implications associated with SHIP1 modulation, we firmly believe that our study, through a rigorous and comprehensive proteomics, transcriptomics and targeted lipidomic analysis of microglia, contributes to the systematic understanding of microglial function in the context of neurodegenerative diseases.
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Enfermedad de Alzheimer , Microglía , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas , Proteoma , Microglía/metabolismo , Animales , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Ratones , Proteoma/metabolismo , Proteoma/análisis , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Ratones Noqueados , Transcriptoma , Fosfatidilinositoles/metabolismo , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Proteómica/métodosAsunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Trasplante Autólogo , Persona de Mediana Edad , FemeninoRESUMEN
Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.
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Evasión Inmune , Leucemia Mieloide Aguda , Animales , Humanos , Ratones , Médula Ósea , Inmunidad Celular , Inmunoterapia , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models. We showed that LAIR-1 agonism drives a unique apoptotic signaling program in leukemic cells that was enhanced in the presence of collagen. NC525 also significantly improved the activity of azacitidine and venetoclax to establish LAIR-1 targeting as a therapeutic strategy for AML that may synergize with standard-of-care therapies.
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Leucemia Mieloide Aguda , Animales , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Células Madre Hematopoyéticas/metabolismo , Transducción de Señal , Modelos Animales de Enfermedad , Células Madre Neoplásicas/metabolismoRESUMEN
INTRODUCTION: The risk of developing Alzheimer's disease is associated with genes involved in microglial function. Inositol polyphosphate-5-phosphatase (INPP5D), which encodes Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is a risk gene expressed in microglia. Because SHIP1 binds receptor immunoreceptor tyrosine-based inhibitory motifs (ITIMs), competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P2, it is a negative regulator of microglia function. Validated inhibitors are needed to evaluate SHIP1 as a potential therapeutic target. METHODS: We identified inhibitors and screened the enzymatic domain of SHIP1. A protein construct containing two domains was used to evaluate enzyme inhibitor potency and selectivity versus SHIP2. Inhibitors were tested against a construct containing all ordered domains of the human and mouse proteins. A cellular thermal shift assay (CETSA) provided evidence of target engagement in cells. Phospho-AKT levels provided further evidence of on-target pharmacology. A high-content imaging assay was used to study the pharmacology of SHIP1 inhibition while monitoring cell health. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties were evaluated to select a compound suitable for in vivo studies. RESULTS: SHIP1 inhibitors displayed a remarkable array of activities and cellular pharmacology. Inhibitory potency was dependent on the protein construct used to assess enzymatic activity. Some inhibitors failed to engage the target in cells. Inhibitors that were active in the CETSA consistently destabilized the protein and reduced pAKT levels. Many SHIP1 inhibitors were cytotoxic either at high concentration due to cell stress or they potently induced cell death depending on the compound and cell type. One compound activated microglia, inducing phagocytosis at concentrations that did not result in significant cell death. A pharmacokinetic study demonstrated brain exposures in mice upon oral administration. DISCUSSION: 3-((2,4-Dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyridine activated primary mouse microglia and demonstrated exposures in mouse brain upon oral dosing. Although this compound is our recommended chemical probe for investigating the pharmacology of SHIP1 inhibition at this time, further optimization is required for clinical studies. Highlights: Cellular thermal shift assay (CETSA) and signaling (pAKT) assays were developed to provide evidence of src homology 2 (SH2) domain-contaning inositol phosphatase 1 (SHIP1) target engagement and on-target activity in cellular assays.A phenotypic high-content imaging assay with simultaneous measures of phagocytosis, cell number, and nuclear intensity was developed to explore cellular pharmacology and monitor cell health.SHIP1 inhibitors demonstrate a wide range of activity and cellular pharmacology, and many reported inhibitors are cytotoxic.The chemical probe 3-((2,4-dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyridine is recommended to explore SHIP1 pharmacology.
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BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Cromosomas Humanos X , Enfermedad de Parkinson , Femenino , Humanos , Masculino , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos , América Latina , Enfermedad de Parkinson/genética , Factores Sexuales , Cromosomas Humanos X/genética , Desequilibrio de Ligamiento/genéticaRESUMEN
The middle corona, the region roughly spanning heliocentric distances from 1.5 to 6 solar radii, encompasses almost all of the influential physical transitions and processes that govern the behavior of coronal outflow into the heliosphere. The solar wind, eruptions, and flows pass through the region, and they are shaped by it. Importantly, the region also modulates inflow from above that can drive dynamic changes at lower heights in the inner corona. Consequently, the middle corona is essential for comprehensively connecting the corona to the heliosphere and for developing corresponding global models. Nonetheless, because it is challenging to observe, the region has been poorly studied by both major solar remote-sensing and in-situ missions and instruments, extending back to the Solar and Heliospheric Observatory (SOHO) era. Thanks to recent advances in instrumentation, observational processing techniques, and a realization of the importance of the region, interest in the middle corona has increased. Although the region cannot be intrinsically separated from other regions of the solar atmosphere, there has emerged a need to define the region in terms of its location and extension in the solar atmosphere, its composition, the physical transitions that it covers, and the underlying physics believed to shape the region. This article aims to define the middle corona, its physical characteristics, and give an overview of the processes that occur there.
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BACKGROUND: Postoperative length of stay is a meaningful patient-centered outcome and an important determinant of healthcare costs. The Surgical Risk Preoperative Assessment System preoperatively predicts 12 postoperative adverse events using 8 preoperative variables, but its ability to predict postoperative length of stay has not been assessed. We aimed to determine whether the Surgical Risk Preoperative Assessment System variables could accurately predict postoperative length of stay up to 30 days in a broad inpatient surgical population. METHODS: This was a retrospective analysis of the American College of Surgeons' National Surgical Quality Improvement Program adult database from 2012 to 2018. A model using the Surgical Risk Preoperative Assessment System variables and a 28-variable "full" model, incorporating all available American College of Surgeons' National Surgical Quality Improvement Program preoperative nonlaboratory variables, were fit to the analytical cohort (2012-2018) using multiple linear regression and compared using model performance metrics. Internal chronological validation of the Surgical Risk Preoperative Assessment System model was conducted using training (2012-2017) and test (2018) datasets. RESULTS: We analyzed 3,295,028 procedures. The adjusted R2 for the Surgical Risk Preoperative Assessment System model fit to this cohort was 93.3% of that for the full model (0.347 vs 0.372). In the internal chronological validation of the Surgical Risk Preoperative Assessment System model, the adjusted R2 for the test dataset was 97.1% of that for the training dataset (0.3389 vs 0.3489). CONCLUSION: The parsimonious Surgical Risk Preoperative Assessment System model can preoperatively predict postoperative length of stay up to 30 days for inpatient surgical procedures almost as accurately as a model using all 28 American College of Surgeons' National Surgical Quality Improvement Program preoperative nonlaboratory variables and has shown acceptable internal chronological validation.
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Pacientes Internos , Complicaciones Posoperatorias , Adulto , Humanos , Tiempo de Internación , Estudios Retrospectivos , Factores de Riesgo , Complicaciones Posoperatorias/epidemiología , Medición de Riesgo/métodosRESUMEN
OBJECTIVES: Epstein-Barr virus-positive large B-cell lymphoma (EBV+ LBCL) is a heterogeneous group of diseases that may resemble classic Hodgkin lymphoma (CHL) both morphologically and immunophenotypically. However, these diseases are treated with different therapies and carry distinct prognoses. We examined CD200 expression by immunohistochemistry in EBV+ LBCL and evaluated its diagnostic utility in the differential diagnosis with CHL. METHODS: CD200 immunohistochemistry was performed on archival material from 20 cases of CHL (11 EBV+, 9 EBV-), 11 cases of EBV+ LBCL, and 10 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS). Staining pattern and intensity (0-3+ scale) were recorded. RESULTS: CD200 positivity was seen in Reed-Sternberg cells in 19 (95%) of 20 cases of CHL, predominantly in a strong (3+, 15/19) and diffuse (>50% of cells, 17/19) pattern. In contrast, CD200 was negative in 8 (73%) of 11 cases of EBV+ LBCL; the 3 positive cases showed 1 to 2+ staining in less than 50% of lesional cells. All cases of DLBCL NOS were negative for CD200. CONCLUSIONS: CD200 may be a useful immunophenotypic marker in differentiating EBV+ LBCL from CHL, with negative to partial/weak staining favoring a diagnosis of EBV+ LBCL and strong diffuse staining favoring a diagnosis of CHL.
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Antígenos CD , Infecciones por Virus de Epstein-Barr , Enfermedad de Hodgkin , Linfoma de Células B Grandes Difuso , Humanos , Infecciones por Virus de Epstein-Barr/diagnóstico , Herpesvirus Humano 4 , Enfermedad de Hodgkin/diagnóstico , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/virología , Antígenos CD/análisisRESUMEN
PURPOSE: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. PATIENTS AND METHODS: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. RESULTS: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. CONCLUSIONS: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.
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Inhibidores de las Cinasas Janus , Mielofibrosis Primaria , Humanos , Anciano , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/metabolismo , Fosfatidilinositol 3-Quinasas , Pirimidinas/uso terapéutico , Nitrilos/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéuticoRESUMEN
BACKGROUND: Safe, efficient, and reliable innovations among donation systems are needed to meet the growing global demand for source plasma. This study assessed the ability of a new donation system to collect appropriate product weights based on the US Food and Drug Administration nomogram for source plasma collections. Procedure duration and safety endpoints were also collected. STUDY DESIGN AND METHODS: The Rika Plasma Donation System (Terumo BCT, Inc., Lakewood, CO) was evaluated in a prospective, open-label, multicenter study. Healthy adults meeting FDA and Plasma Protein Therapeutics Association requirements for source plasma donor eligibility were consented and enrolled in the study resulting in 124 evaluable products. RESULTS: The target product collection weights (ie, including plasma and anticoagulant) by participant weight category were: 705 g (110-149 lbs), 845 g (150-174 lbs), and 900 g (≥175 lbs). The mean reported product collection weights by participant weight category were 705.0 ± 0.00, 845.0 ± 0.20, and 899.9 ± 0.31 g, respectively. The mean overall procedure time was 31.5 ± 5.41 minutes. The mean procedure times by participant weight category were 25.6 ± 3.13, 30.5 ± 4.45, and 33.7 ± 4.80 minutes, respectively. Procedure-emergent adverse events (PEAEs) occurred in five participants. All PEAEs were consistent with known risks for apheresis donation, and none were related to the donation system. CONCLUSIONS: The new donation system collected the target product collection weight in 100% of evaluable products. The mean procedure collection time was 31.5 minutes. The system is a new efficient platform that consistently collects the appropriate weight of the source plasma.
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Eliminación de Componentes Sanguíneos , Adulto , Humanos , Estudios Prospectivos , Eliminación de Componentes Sanguíneos/métodos , Donantes de SangreRESUMEN
Although allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. Patients with TP53-mutated (TP53MUT) MDS/AML are at particularly high risk, yet fewer TP53MUT patients undergo HCT compared with poor-risk TP53-wild type (TP53WT) patients. We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting the rate of HCT and thus investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT. In this single-center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n = 352), HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (ORs) for factors associated with HLA typing, HCT, and pretransplantation infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and those without TP53 mutations. Overall, significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%; P = .028). Development of infection was significantly associated with decreased odds of HCT (OR, .42; 95% CI, .19 to .90) and worse overall survival (hazard ratio, 1.46; 95% CI, 1.09 to 1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR, 2.18; 95% CI, 1.21 to 3.93), bacterial pneumonia (OR, 1.83; 95% CI, 1.00 to 3.33), and invasive fungal infection (OR, 2.64; 95% CI, 1.34 to 5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% versus 19%; P = .005). With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.
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Deficiencia GATA2 , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Humanos , Estudios Retrospectivos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación/genética , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.
First study comparing genetic profiles of MS and AML with a common disease-defining lesion.NPM1Mut MS may be genetically distinct from NPM1Mut AML.NPM1Mut MS may have inferior overall survival compared to NPM1Mut AML.