Serial Quantitation of Plasma Microbial Cell-Free DNA Before and After Diagnosis of Pulmonary Invasive Mold Infections After Hematopoietic Cell Transplant.

BACKGROUND: Plasma microbial cell-free DNA sequencing (mcfDNA-Seq) is a noninvasive test for microbial diagnosis of invasive mold infection (IMI). The utility of mcfDNA-Seq for predicting IMI onset and the clinical implications of mcfDNA concentrations are unknown. METHODS: We retrospectively tested plasma from hematopoietic cell transplant (HCT) recipients with pulmonary IMI and ≥1 mold identified by mcfDNA-Seq in plasma collected within 14 days of clinical diagnosis. Samples collected from up to 4 weeks before and 4 weeks after IMI diagnosis were evaluated using mcfDNA-Seq. RESULTS: Thirty-five HCT recipients with 39 IMIs (16 Aspergillus and 23 non-Aspergillus infections) were included. Pathogenic molds were detected in 38%, 26%, 11%, and 0% of samples collected during the first, second, third, and fourth week before clinical diagnosis, respectively. In non-Aspergillus infections, median mcfDNA concentrations in samples collected within 3 days of clinical diagnosis were higher in infections with versus without extrapulmonary spread (4.3 vs 3.3 log10 molecules per microliter [mpm], P = .02), and all patients (8/8) with mcfDNA concentrations >4.0 log10 mpm died within 42 days after clinical diagnosis. CONCLUSIONS: Plasma mcfDNA-Seq can identify pathogenic molds up to 3 weeks before clinical diagnosis of pulmonary IMI. Plasma mcfDNA concentrations may correlate with extrapulmonary spread and mortality in non-Aspergillus IMI.

Real-world effectiveness of preemptive therapy (PET) for cytomegalovirus (CMV) disease prevention in CMV high-risk donor seropositive/recipient seronegative (D+R-) liver transplant recipients (LTxR).

BACKGROUND: Despite superiority of preemptive therapy (PET) compared to universal prophylaxis for prevention of cytomegalovirus (CMV) disease in the CAPSIL randomized trial among CMV D+R- liver transplant recipients (LTxRs), real-world effectiveness may be lower because of logistical concerns about feasibility of PET. METHODS: We retrospectively assessed PET as standard clinical care at a single transplant center among 50 consecutive adult CMV D+R- LTxRs undergoing a first liver transplant between 4/4/2019 and 5/18/2021 and compared outcomes and adherence to those randomized to PET in the CAPSIL study (N = 100). The primary outcome was CMV disease and secondary outcomes were biopsy-confirmed acute allograft rejection, retransplant, invasive fungal infections, and death, all assessed by 1-year post-transplant. Exploratory outcomes included virologic parameters and measures of adherence to protocol-specified CMV qPCR monitoring. RESULTS: Baseline characteristics were similar between groups. The cumulative incidence of CMV disease at 1-year post-transplant was 4/50 (8%) versus 9/100 (9%) in the real-world and CAPSIL cohorts, respectively, p = 1.0. The rate of breakthrough CMV disease during the 100-day PET period was low (2/50 [4%]) and similar to the PET cohort from the CAPSIL study (3/100 [3%]).  All secondary and exploratory outcomes were not significantly different between the real-world and CAPSIL PET cohorts. CONCLUSIONS: In this first reported study of real-world PET, the feasibility and effectiveness for CMV disease prevention and for other clinical outcomes in CMV D+R- LTxRs were similar to those reported with PET in a clinical trial. Additional studies to confirm feasibility and generalizability in other settings are warranted.

Combined assessment of Epstein-Barr virus viral capsid antigen and Epstein-Barr virus nuclear antigen-1 serology for post-transplant lymphoproliferative disorder risk stratification in adult solid organ transplant recipients.

BACKGROUND: Epstein-Barr virus (EBV) seronegative solid organ transplant recipients (SOTRs) are at increased risk for post-transplant lymphoproliferative disorder (PTLD). Assays for EBV serostatus assess antibody to both EBV viral capsid antigen (VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1), but PTLD risk among SOT recipients with discordant VCA and EBNA-1 results is unknown. METHODS: We performed a retrospective, single-center cohort study to determine the risk of PTLD among adult (≥ 18 years) SOTRs with discordant pre-transplant VCA and EBNA-1 IgG compared to that of SOTRs with concordantly negative or concordantly positive serology using univariable and multivariable Cox-proportional hazards models. RESULTS: Of 4106 SOTRs, the number (%) who were concordantly positive, concordantly negative, and discordant was 3787 (92.2%), 149 (3.6%), and 170 (4.2%), respectively. The adjusted hazard of PTLD was significantly higher among discordant SOTRs compared to concordantly positive SOTRs (aHR 2.6, 95% CI 1.04-6.6, p =.04) and lower compared to concordantly negative SOTRs (aHR 0.27, 95% CI 0.10-0.76, p <.001). The adjusted hazard of EBV+ PTLD among those with discordant serology was also significantly higher compared to the concordantly positive cohort (aHR 3.53, 95% CI 1.04-12.0, p =.04) and significantly lower compared to the concordantly negative cohort (aHR 0.23, 95% CI 0.06-0.82, p =.02). CONCLUSIONS: Risk of PTLD among SOTRs with discordant VCA and EBNA-1 may be intermediate between those with concordantly positive and negative serology. If confirmed in future studies, revision of national EBV serology reporting to include both VCA and EBNA results may be needed to optimize PTLD risk stratification.

American Society of Transplantation and Cellular Therapy Series, 2: Management and Prevention of Aspergillosis in Hematopoietic Cell Transplantation Recipients.

The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A completely fresh approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQs), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. This second guideline in the series focuses on invasive aspergillosis, a potentially life-threatening infection in the peri-HCT period. The relevant risk factors, diagnostic considerations, and prophylaxis and treatment approaches are reviewed.

Pulmonary and vascular effects of acute ozone exposure in diabetic rats fed an atherogenic diet.

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.

Liquid Biopsy for Invasive Mold Infections in Hematopoietic Cell Transplant Recipients With Pneumonia Through Next-Generation Sequencing of Microbial Cell-Free DNA in Plasma.

BACKGROUND: Noninvasive diagnostic options are limited for invasive mold infections (IMIs). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT). METHODS: We retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq next-generation sequencing in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of proven/probable Aspergillus IMI (n = 51), proven/probable non-Aspergillus IMI (n = 24), possible IMI (n = 20), and non-IMI controls (n = 19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported. RESULTS: Among 75 patients with proven/probable pulmonary IMI, mcfDNA-Seq detected ≥1 pathogenic mold in 38 patients (sensitivity, 51% [95% confidence interval {CI}, 39%-62%]). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for proven/probable non-Aspergillus IMI (sensitivity, 79% [95% CI, 56%-93%]) compared with Aspergillus IMI (sensitivity, 31% [95% CI, 19%-46%]). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples, suggesting a high specificity (95% CI, 82%-100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPVs) of 81%-99%. The mcfDNA-Seq assay was complementary to serum galactomannan index testing; in combination, they were positive in 84% of individuals with proven/probable pulmonary IMI. CONCLUSIONS: Noninvasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus species.

Human Herpesvirus 6B and Lower Respiratory Tract Disease After Hematopoietic Cell Transplantation.

PURPOSE: Human herpesvirus 6B (HHV-6B) DNA is frequently detected in bronchoalveolar lavage fluid (BALF) from immunocompromised subjects with lower respiratory tract disease (LRTD). Whether HHV-6B is a pulmonary pathogen is unclear. METHODS: We tested BALF for HHV-6B DNA using polymerase chain reaction in allogeneic hematopoietic cell transplantation (HCT) recipients who underwent a BAL for evaluation of LRTD from 1992 to 2015. We used multivariable proportional hazards models to evaluate the association of HHV-6B+ BALF with overall mortality, death from respiratory failure, and the effect of anti-HHV-6B antivirals on these outcomes. We used branched-chain RNA in situ hybridization to detect HHV-6 messenger RNA (U41 and U57 transcripts) in lung tissue. RESULTS: We detected HHV-6B+ BALF from 147 of 553 (27%) individuals. Subjects with HHV-6B+ BALF, with or without copathogens, had significantly increased risk of overall mortality (adjusted hazard ratio [aHR], 2.18; 95% CI, 1.41-3.39) and death from respiratory failure (aHR, 2.50; 95% CI, 1.56-4.01) compared with subjects with HHV-6B- BALF. Subjects with HHV-6B+ BALF who received antivirals within 3 days pre-BAL had an approximately 1 log10 lower median HHV-6B BALF viral load, as well as a lower risk of overall mortality (aHR, 0.42; 95% CI, 0.16-1.10), compared with subjects with HHV-6B+ BALF not receiving antivirals. We detected intraparenchymal HHV-6 gene expression by RNA in situ hybridization in lung tissue in all three tested subjects with HHV-6B+ BALF and sufficient tissue RNA preservation. CONCLUSION: These data provide evidence that HHV-6B detection in BALF is associated with higher mortality in allogeneic hematopoietic cell transplantation recipients with LRTD. Definitive evidence of causation will require a randomized prevention or treatment trial.

Gynecologic cancers and solid organ transplantation.

Solid organ transplant (SOT) recipients have an approximately 2-fold greater risk of developing and dying from a malignancy compared to the general population. Among the gynecologic cancers, including uterine, cervical, vaginal, vulvar, and ovarian, the HPV-related cancers are known to increase among women posttransplant compared to women in the general population, but less is known about the risk of uterine and ovarian cancers. This review provides an overview of the epidemiology of gynecologic cancers after solid organ transplantation, as well as the pathophysiology, management, and specific risk factors associated with these cancers. Closer surveillance for cervical cancers is warranted and larger studies are needed to assess whether and how uterine and ovarian cancers are associated with excess incidence and mortality. Such studies may lead to improvements in screening, prevention, and treatment before and after transplantation.

Clinical characteristics and outcomes of late-onset BK virus nephropathy in kidney and kidney-pancreas transplant recipients.

BACKGROUND: BK virus nephropathy (BKPyVAN) is a major complication in kidney transplant recipients (KTR) and typically occurs within 1 year of transplant. Guidelines vary in recommendations for BKPyV screening beyond 1 year. A systematic characterization of risk factors and outcomes of late-onset (>1 year) BKPyVAN has not previously been reported. METHODS: We retrospectively compared characteristics and outcomes of early- (<1 year) and late-onset BKPyVAN (definitive [biopsy-confirmed] or presumptive [plasma BKPyV >10 000 copies/mL]) in a cohort of 671 KTR and simultaneous kidney-pancreas transplant (SPK) recipients between 2008 and 2013 at a single US transplant center. Proportions were compared using Chi-square or Fisher's exact test with P < .05 considered significant. RESULTS: BKPyVAN was diagnosed in 96 (14.3%) patients (proven 16.7%, presumptive 83.3%): 79 (82.3%) early- and 17 (17.7%) late-onset. The proportion with late-onset BKPyVAN was significantly higher among SPK than KTR (4 of 7 [57.1%] vs 13 of 89 [14.6%], P = .017). Late-onset represented "de novo" infection (no BKPyV detection within the first year) in 14 (82.4%) and progression of earlier lower grade BKPyV reactivation in 3 (17.6%). Clinical outcomes were similar for early- and late-onset BKPyVAN (P > .05 all comparisons). In a pooled analysis of prior studies of BKPyVAN in SPK recipients, 62.9% (17 of 27) were late-onset. CONCLUSION: A significant proportion of BKPyVAN is late-onset, especially among SPK recipients, and supports a longer duration of BKPyV monitoring for SPK recipients than recommended in some guidelines.

Current state of screening high-ACE youth and emerging adults in primary care.

BACKGROUND AND PURPOSE: Trauma comes in many forms, including interpersonal, community, and institutional trauma. The adverse childhood event (ACE) studies demonstrated that adverse experiences in childhood can have a profound, cumulative impact on the course of health and development over a lifetime. It is critical for healthcare providers, such as nurse practitioners (NPs), working in primary care to screen adolescents and emerging adults for a history of ACEs and trauma. A review of current assessment tools used in assessing this population in health settings is needed to determine how screening for ACEs is being performed. CONCLUSIONS: Clinically efficient tools for screening and assessment of high-ACE youth in primary care settings are lacking.  Developing a process to assess ACEs, risk behaviors, and physical and mental health status that is efficient to use during a time limited clinical visit is an important step in providing holistic care to a challenging population. IMPLICATIONS FOR PRACTICE: Primary care NPs are in the perfect position to implement assessments of ACEs through trauma-informed nursing care. ACE assessment in clinical practice will provide vital information to guide the development of tailored interventions for reducing risk behaviors and mitigate the long-term impacts of ACEs.

Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation.

Invasive aspergillosis (IA) is a significant cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Previous studies have reported an association between IA development and single nucleotide polymorphisms (SNPs), but many SNPs have not been replicated in a separate cohort. The presence of a positive serum galactomannan assay (SGM+) has also been associated with a worse prognosis in patients with IA, and genetic determinants in this subset of patients have not been systematically studied. The study cohort included 2609 HCT recipients and their donor pairs: 483 with proven/probable IA (183 SGM+) and 2126 with no IA by standard criteria. Of 25 SNPs previously published, we analyzed 20 in 14 genes that passed quality control. Samples were genotyped via microarray, and SNPs that could not be genotyped were imputed. The primary aim was to replicate SNPs associated with proven/probable IA at 2 years; secondary goals were to explore the associations using an end point of SGM+ IA or proven/probable IA using a different genetic model or time to IA (3 months vs 2 years) compared with the original study. Two SNPs in 2 genes (PTX3, CLEC7a) were replicated. Thirteen SNPs in 9 genes had an association at P ≤ .05 using the secondary aims (PTX3, CLEC7a, CD209, CXCL10, TLR6, S100B, IFNG, PLG, TNFR1), with hazard ratios ranging from 1.2 to 3.29. Underlying genetic differences can influence development of IA following HCT. Identification of genetic predispositions to IA could have important implications in donor screening, risk stratification of recipients, monitoring, and prophylaxis.

Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies.

Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006 were tested for 28 pathogens (3 bacteria and 25 viruses) by quantitative polymerase chain reaction and for Aspergillus by galactomannan assay. Research BALs from 21 asymptomatic HCT patients served as controls. Among 69 HCT patients with IPS, 39 (56.5%) had a pathogen detected. The most frequent pathogens were human herpesvirus-6 (HHV-6) (N = 20 [29%]) followed by human rhinovirus (HRV), cytomegalovirus (CMV), and Aspergillus (N = 8 [12%] in each). HHV-6 and HRV were rarely detected in controls, whereas CMV and Aspergillus were occasionally detected with low pathogen load. Patients with pathogens had worse day-100 survival than those without (hazard ratio, 1.88; P = .03). Mortality in patients with only pathogens of "uncertain" significance in lung was similar to that in patients with pathogens of "established" significance. Metagenomic next-generation sequencing did not reveal additional significant pathogens. Our study demonstrated that approximately half of patients with IPS had pathogens detected in BAL, and pathogen detection was associated with increased mortality. Thus, an expanded infection detection panel can significantly increase the diagnostic precision for idiopathic pneumonia.

A patient self-collection method for longitudinal monitoring of respiratory virus infection in solid organ transplant recipients.

BACKGROUND: Methods for the longitudinal study of respiratory virus infections are cumbersome and limit our understanding of the natural history of these infections in solid organ transplant (SOT) recipients. OBJECTIVES: To assess the feasibility and patient acceptability of self-collected foam nasal swabs for detection of respiratory viruses in SOT recipients and to define the virologic and clinical course. STUDY DESIGN: We prospectively monitored the course of symptomatic respiratory virus infection in 18 SOT patients (14 lung, 3 liver, and 1 kidney) using patient self-collected swabs. RESULTS: The initial study sample was positive in 15 patients with the following respiratory viruses: rhinovirus (6), metapneumovirus (1), coronavirus (2), respiratory syncytial virus (2), parainfluenza virus (2), and influenza A virus (2). One hundred four weekly self-collected nasal swabs were obtained, with a median of 4 samples per patient (range 1-17). Median duration of viral detection was 21 days (range 4-77 days). Additional new respiratory viruses detected during follow-up of these 15 patients included rhinovirus (3), metapneumovirus (2), coronavirus (1), respiratory syncytial virus (1), parainfluenza virus (1), and adenovirus (1). Specimen collection compliance was good; 16/18 (89%) patients collected all required specimens and 79/86 (92%) follow-up specimens were obtained within the 7 ± 3 day protocol-defined window. All participants agreed or strongly agreed that the procedure was comfortable, simple, and 13/14 (93%) were willing to participate in future studies using this procedure. CONCLUSION: Self-collected nasal swabs provide a convenient, feasible, and patient-acceptable methodology for longitudinal monitoring of upper respiratory virus infection in SOT recipients.

The Rapid Assessment for Adolescent Preventive Services (RAAPS): providers' assessment of its usefulness in their clinical practice settings.

INTRODUCTION: The purpose of this study was to evaluate health providers' use of the Rapid Assessment for Adolescent Preventive Services (RAAPS) screening tool to identify adolescent high-risk behaviors, its ease of use and efficiency, and its impact on provider/patient discussions of sensitive risk behaviors. METHOD: This mixed methods descriptive study used an online survey to assess providers' use of the RAAPS and their perspectives on its implementation and effect on adolescent-provider communication. The survey was completed by providers from a variety of settings across the United States (N = 201). RESULTS: Quantitative and qualitative analyses indicated that the RAAPS facilitated identification of risk behaviors and risk discussions and provided efficient and consistent assessments; 86% of providers believed that the RAAPS positively influenced their practice. DISCUSSION: Adoption of the RAAPS in practice settings could lead to more effective adolescent preventive services by giving providers a tool to systematically assess and identify adolescents at risk. Implementation of RAAPS offers health providers an efficient, consistent, and "adolescent friendly" way to identify risky behaviors and open the discussion needed to tailor interventions to meet their needs.

The serum galactomannan index predicts mortality in hematopoietic stem cell transplant recipients with invasive aspergillosis.

We examined the relationship between serum and bronchoalveolar lavage (BAL) galactomannan index (GMI) values and mortality in allogeneic hematopoietic cell transplant recipients with invasive pulmonary aspergillosis. Using a clinical sign and symptom-initiated approach, we found that the serum but not the BAL GMI level correlated with 42- and 180-day patient mortality.

Perceived difficulty quitting predicts enrollment in a smoking-cessation program for patients with head and neck cancer.

PURPOSE/OBJECTIVES: To determine the predictors of participation in a smoking-cessation program among patients with head and neck cancer. DESIGN: This cross-sectional study is a substudy of a larger, randomized trial of patients with head and neck cancer that determined the predictors of smokers' participation in a cessation intervention. SETTING: Otolaryngology clinics at three Veterans Affairs medical centers (Ann Arbor, MI, Gainesville, FL, and Dallas, TX), and the University of Michigan Hospital in Ann Arbor. SAMPLE: 286 patients who had smoked within six months of the screening survey were eligible for a smoking-cessation intervention. METHODS: Descriptive statistics and bivariate and multivariate logistic regression were used to determine the independent predictors of smokers' participation in an intervention study. MAIN RESEARCH VARIABLES: Perceived difficulty quitting (as a construct of self-efficacy), health behaviors (i.e., smoking and problem drinking), clinical characteristics (i.e., depression and cancer site and stage), and demographic variables. FINDINGS: Forty-eight percent of those eligible participated. High perceived difficulty quitting was the only statistically significant predictor of participation, whereas problem drinking, lower depressive symptoms, and laryngeal cancer site approached significance. CONCLUSIONS: Special outreach may be needed to reach patients with head and neck cancer who are overly confident in quitting, problem drinkers, and patients with laryngeal cancer. IMPLICATIONS FOR NURSING: Oncology nurses are in an opportune position to assess patients' perceived difficulty quitting smoking and motivate them to enroll in cessation programs, ultimately improving quality of life, reducing risk of recurrence, and increasing survival for this population.

Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia.

The Additional sex combs like 1 (Asxl1) gene is 1 of 3 mammalian homologs of the Additional sex combs (Asx) gene of Drosophila. Asx is unusual because it is required to maintain both activation and silencing of Hox genes in flies and mice. Asxl proteins are characterized by an amino terminal homology domain, by interaction domains for nuclear receptors, and by a C-terminal plant homeodomain protein-protein interaction domain. A recent study of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) revealed a high incidence of truncation mutations that would delete the PHD domain of ASXL1. Here, we show that Asxl1 is expressed in all hematopoietic cell fractions analyzed. Asxl1 knockout mice exhibit defects in frequency of differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors. We do not detect effects on hematopoietic stem cells, or in peripheral blood. Notably, we do not detect severe myelodysplastic phenotypes or leukemia in this loss-of-function model. We conclude that Asxl1 is needed for normal hematopoiesis. The mild phenotypes observed may be because other Asxl genes have redundant function with Asxl1, or alternatively, MDS or oncogenic phenotypes may result from gain-of-function Asxl mutations caused by genomic amplification, gene fusion, or truncation of Asxl1.

A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11.

The Additional sex combs (Asx) gene of Drosophila is an Enhancer of trithorax and Polycomb (ETP), and is required to maintain activation and silencing of homeotic loci. The molecular basis of this dual function is not understood. Here, we identify a human homolog of Asx, termed ADDITIONAL SEX COMBS-LIKE 1 (ASXL1). Overall, the amino acid sequence of ASXL1 has 21% identity and 41% similarity to Drosophila ASX. The ASXL1 protein contains a 118 amino acid conserved amino terminal region of unknown function that we term the ASX homology domain (ASXH) that contains two LXXLL consensus sequences for nuclear receptor binding. ASXL1 also contains a conserved C-terminal cysteine cluster that is a variant of the PHD domain. Three ASXL1 transcripts of differing size are detected, which are widely expressed in adult tissues. ASXL1 maps to chromosome 20q11, a region frequently amplified in human tumors. Interestingly, ASXL1 is overexpressed in cell lines derived from carcinomas.