Long-term outcomes of anterior latissimus dorsi tendon transfer for irreparable subscapularis tears.

Aims: Favourable short-term outcomes have been reported following latissimus dorsi tendon transfer for patients with an irreparable subscapularis (SSC) tendon tear. The aim of this study was to investigate the long-term outcomes of this transfer in these patients. Methods: This was a retrospective study involving 30 patients with an irreparable SSC tear and those with a SSC tear combined with a reparable supraspinatus tear, who underwent a latissimus dorsi tendon transfer. Clinical scores and active range of motion (aROM), SSC-specific physical examination and the rate of return to work were assessed. Radiological assessment included recording the acromiohumeral distance (AHD), the Hamada grade of cuff tear arthropathy and the integrity of the transferred tendon. Statistical analysis compared preoperative, short-term (two years), and final follow-up at a mean of 8.7 years (7 to 10). Results: There were significant improvements in clinical scores, in the range and strength of internal rotation and aROM compared with the preoperative values in the 26 patients (87%) who were available for long-term follow-up. These improvements were maintained between short- and long-term follow-ups. Although there was a decreased mean AHD of 7.3 mm (SD 1.5) and an increased mean Hamada grade of 1.7 (SD 0.5) at final follow-up, the rate of progression of cuff tear arthropathy remained low-grade. Comparison between the isolated SSC and combined SSC and reparable supraspinatus tear groups showed no significant differences. At final follow-up, one patient (3.8%) had undergone revision surgery to a reverse shoulder arthroplasty (RSA). No neurological complications were associated with the procedure. Conclusion: Latissimus dorsi transfer for an irreparable SSC tendon tear resulted in a significant clinical improvement, particularly in pain, range and strength of internal rotation and aROM, which were maintained over a mean of 8.7 years following surgery. Given that this was a long-term outcome study, there was a low-grade progression in the rate of cuff tear arthropathy. Thus, the long-term clinical efficacy of latissimus dorsi tendon transfer in patients with irreparable SSC was confirmed as a joint-preserving procedure for these patients, suggesting it as an effective alternative to RSA in young, active patients without degenerative changes of the glenohumeral joint.

Childhood vaccination among Polish immigrants in Norway: a qualitative study.

BACKGROUND: Confidence in childhood vaccination is high in Norway and the Norwegian Childhood Immunization Programme (NCIP) achieves high overall coverage rates. However, lower coverage has been observed for some immigrant groups, including Polish immigrants who represent the largest immigrant group in Norway. Anti-vaccine sentiments and increased refusal of mandatory childhood vaccination has been on the rise in Poland, but it is unknown whether such attitudes also apply to Polish immigrants in Norway, as they experience a different vaccination policy and perhaps also different attitudes to vaccines. This qualitative study aims to explore attitudes towards childhood vaccination in Norway among Polish immigrants. METHODS: We interviewed 15 Polish parents living in Norway in 2022. We recruited the participants by purposive sampling and analyzed the interviews by reflexive thematic analysis. RESULTS: Three themes were identified: views of childhood vaccination, vaccine hesitancy, and differences in childhood vaccination between Poland and Norway. Overall, the participants favored childhood vaccination and viewed most of the vaccines included in the NCIP as safe and reliable. Human papilloma virus, meningococcal and pneumococcal vaccines were declined by some of the parents. Comparisons of childhood vaccination in Poland and Norway was evident in many of the interviews, especially among parents whose children had received vaccines in both countries. The participants were well acquainted with the NCIP, favored voluntary childhood vaccination, and the majority expressed a high level of trust in Norwegian health authorities. CONCLUSIONS: Polish immigrants to Norway generally expressed positive views about childhood vaccination. Non-vaccination was related to lack of knowledge and/or unfamiliarity with certain vaccines and not with anti-vaccine sentiments or conspiracy theories. The study highlights how parents' knowledge, in combination with norms and trends from both birth country and country of residence, influence parents' decision making about vaccination.

Persistent Pain After Breast Cancer Treatment, an Underreported Burden for Breast Cancer Survivors.

BACKGROUND: Many patients who have undergone surgery experience persistent pain after breast cancer treatment (PPBCT). These symptoms often remain unnoticed by treating physician(s), and the pathophysiology of PPBCT remains poorly understood. The purpose of this study was to determine prevalence of PPBCT and examine the association between PPBCT and various patient, tumor, and treatment characteristics. PATIENTS AND METHODS: We conducted a questionnaire-based cross-sectional study enrolling patients with breast cancer treated at Máxima Medical Center between 2005 and 2016. PPBCT was defined as pain in the breast, anterior thorax, axilla, and/or medial upper arm that persists for at least 3 months after surgery. Tumor and treatment characteristics were derived from the Dutch Cancer Registry and electronic patient files. RESULTS: Between February and March 2019, a questionnaire was sent to 2022 women, of whom 56.5% responded. Prevalence of PPBCT among the responders was 37.9%, with 50.8% reporting moderate to severe pain. Multivariable analyses showed that women with signs of anxiety, depression or a history of smoking had a higher risk of experiencing PPBCT. Women aged 70 years or older at diagnosis were significantly less likely to report PPBCT compared with younger women. No significant association was found between PPBCT and treatment characteristics, including type of axillary surgery and radiotherapy. CONCLUSIONS: A considerable percentage of patients with breast cancer experience PPBCT. Women with signs of anxiety or depression and women with a history of smoking are more likely to report PPBCT. Further research is required to understand the underlying etiology and to improve prevention and treatment strategies for PPBCT.

Predictors of maternal pertussis vaccination acceptance among pregnant women in Norway.

Maternal vaccination against pertussis is safe and provides effective protection against pertussis for the newborn, but the vaccine coverage rate remains generally low. Norway is currently planning for introduction of routine maternal pertussis vaccination. To assess maternal pertussis vaccination acceptance among pregnant Norwegian women, we surveyed women at 20-40 weeks gestation in 2019. Among the 1,148 pregnant women participating in this cross-sectional study, 73.8% reported they would accept pertussis vaccination during pregnancy if it was recommended, 6.9% would not accept and 19.2% were undecided. Predictors for low likelihood of accepting pertussis vaccination during pregnancy included low confidence in health authorities and in maternal pertussis vaccination safety and effectiveness, low awareness and adherence to influenza vaccination during pregnancy, and low awareness of pertussis vaccination. The major reasons reported for not accepting or being undecided about maternal pertussis vaccination were lack of information on vaccine safety for both mother and child. Most women reported that they would consult their general practitioner or a midwife for information if they were offered maternal pertussis vaccination. General practitioners and midwives were also regarded as the most trustworthy sources of information if the women were in doubt about accepting vaccination. We conclude that information addressing safety concerns and raising awareness about maternal pertussis vaccination could increase acceptance of maternal pertussis vaccination. Our findings highlight the pivotal role of the antenatal and primary health care services in providing such information to pregnant women.

Sociodemographic characteristics associated with cervical cancer screening participation by send-to-all and opt-in HPV self-sampling: Who benefits? Results from a randomized controlled trial among long-term non-attending women in Norway.

With the objective to investigate associations between sociodemographic characteristics and participation in interventions designed to increase participation in cervical cancer screening among under-screened women, we randomized a random sample of 6000 women in Norway aged 35-69 years who had not attended cervical screening for ≥10 years to receive either (i) a reminder to attend regular screening (control), (ii) an offer to order a self-sampling kit (opt-in), or (iii) a self-sampling kit unsolicited (send-to-all). We analyzed how sociodemographic characteristics were associated with screening participation within and between screening arms. In the send-to-all arm, increased screening participation ranged from 17.1% (95% confidence interval [95% CI] = 10.3% to 23.8%) to 30.0% (95% CI = 21.5% to 38.6%) between sociodemographic groups. In the opt-in arm, we observed smaller, and at times, non-significant increases within the range 0.7% (95% CI = -5.8% to 7.3%) to 19.1% (95% CI = 11.6% to 26.7%). In send-to-all versus control comparisons, there was greater increase in participation for women in the workforce versus not (6.1%, 95% CI = 1.6% to 10.6%), with higher versus lower income (7.6%, 95% CI = 2.2% to 13.1%), and with university versus primary education (8.5%, 95% CI = 2.4% to 14.6%). In opt-in versus control comparisons, there was greater increase in participation for women in the workforce versus not (4.6%, 95% CI = 0.7% to 8.5%), with higher versus lower income (6.3%, 95% CI = 1.5% to 11.1%), but lower increase for Eastern European versus Norwegian background (-12.7%, 95% CI = -19.7% to -5.7%). Self-sampling increased cervical screening participation across all sociodemographic levels, but inequalities in participation should be considered when introducing self-sampling, especially with the goal to reach long-term non-attending women.

Vaccine coverage among children born to immigrant parents in Norway, 2000-2020.

BACKGROUND: The Norwegian Childhood Immunization Program maintains a high national coverage of 95-97% in the most recent years. Whether there are subgroups with lower uptake is less studied. This study examines pertussis and measles vaccination coverage among six immigrant groups in Norway. These vaccines are normally administered as part of different combination vaccines and their coverage rate indicate the national vaccination coverage against a range of additional infections. METHODS: Data from the Norwegian National Population Register were linked at individual level with vaccination data from the Norwegian Immunisation Registry. The final sample consisted of 53,052 children born during 2000-2018 in Norway to parents who were born in Iraq, Lithuania, Pakistan, Poland, Somalia, or Vietnam. Vaccination coverage was measured at 2-years of age. Multivariate linear regression was utilized to estimate the relationship between vaccinations status, year of birth, gender, mother's length of residency in Norway, and area of residence. RESULTS: At two years of age, the majority of the children were vaccinated. Coverage among the groups varied at, above, and below the national average for the two vaccines. For most of the years examined, children born by parents from Lithuania, Poland, and Somalia had lower coverage for the measles vaccine (range 81-84% in 2020) than the national level (97% in 2020). Children born by parents from the Eastern-European countries also had lower coverage than the national level for the pertussis vaccine (range 87-89% in 2020). DISCUSSION: This study illustrates how subgroups with lower vaccination coverage may exists within a well-established vaccination program with high national coverages. Differences in coverage were found for both vaccines, but the differences were more pronounced for the measles vaccine. The high vaccination coverage in Norway provides indirect protection through herd immunity for unvaccinated individuals, however, the lower vaccination coverage in some immigrant groups is a concern.

Proinflammatory cytokines suppress nonsense-mediated RNA decay to impair regulated transcript isoform processing in pancreatic ß cells.

Introduction: Proinflammatory cytokines are implicated in pancreatic ß cell failure in type 1 and type 2 diabetes and are known to stimulate alternative RNA splicing and the expression of nonsense-mediated RNA decay (NMD) components. Here, we investigate whether cytokines regulate NMD activity and identify transcript isoforms targeted in ß cells. Methods: A luciferase-based NMD reporter transiently expressed in rat INS1(832/13), human-derived EndoC-ßH3, or dispersed human islet cells is used to examine the effect of proinflammatory cytokines (Cyt) on NMD activity. The gain- or loss-of-function of two key NMD components, UPF3B and UPF2, is used to reveal the effect of cytokines on cell viability and function. RNA-sequencing and siRNA-mediated silencing are deployed using standard techniques. Results: Cyt attenuate NMD activity in insulin-producing cell lines and primary human ß cells. These effects are found to involve ER stress and are associated with the downregulation of UPF3B. Increases or decreases in NMD activity achieved by UPF3B overexpression (OE) or UPF2 silencing raise or lower Cyt-induced cell death, respectively, in EndoC-ßH3 cells and are associated with decreased or increased insulin content, respectively. No effects of these manipulations are observed on glucose-stimulated insulin secretion. Transcriptomic analysis reveals that Cyt increases alternative splicing (AS)-induced exon skipping in the transcript isoforms, and this is potentiated by UPF2 silencing. Gene enrichment analysis identifies transcripts regulated by UPF2 silencing whose proteins are localized and/or functional in the extracellular matrix (ECM), including the serine protease inhibitor SERPINA1/α-1-antitrypsin, whose silencing sensitizes ß-cells to Cyt cytotoxicity. Cytokines suppress NMD activity via UPR signaling, potentially serving as a protective response against Cyt-induced NMD component expression. Conclusion: Our findings highlight the central importance of RNA turnover in ß cell responses to inflammatory stress.

Proinflammatory Cytokines Suppress Nonsense-Mediated RNA Decay to Impair Regulated Transcript Isoform Processing in Pancreatic ß-Cells.

Proinflammatory cytokines are implicated in pancreatic ß-cell failure in type 1 and type 2 diabetes and are known to stimulate alternative RNA splicing and the expression of Nonsense-Mediated RNA Decay (NMD) components. Here, we investigate whether cytokines regulate NMD activity and identify transcript isoforms targeted in ß-cells. A luciferase-based NMD reporter transiently expressed in rat INS1(832/13), human-derived EndoC-ßH3 or dispersed human islet cells is used to examine the effect of proinflammatory cytokines (Cyt) on NMD activity. Gain- or loss-of function of two key NMD components UPF3B and UPF2 is used to reveal the effect of cytokines on cell viability and function. RNA-sequencing and siRNA-mediated silencing are deployed using standard techniques. Cyt attenuate NMD activity in insulin-producing cell lines and primary human ß-cells. These effects are found to involve ER stress and are associated with downregulation of UPF3B. Increases or decreases in NMD activity achieved by UPF3B overexpression (OE) or UPF2 silencing, raises or lowers Cyt-induced cell death, respectively, in EndoC-ßH3 cells, and are associated with decreased or increased insulin content, respectively. No effects of these manipulations are observed on glucose-stimulated insulin secretion. Transcriptomic analysis reveals that Cyt increase alternative splicing (AS)-induced exon skipping in the transcript isoforms, and this is potentiated by UPF2 silencing. Gene enrichment analysis identifies transcripts regulated by UPF2 silencing whose proteins are localized and/or functional in extracellular matrix (ECM) including the serine protease inhibitor SERPINA1/α-1-antitrypsin, whose silencing sensitises ß-cells to Cyt cytotoxicity. Cytokines suppress NMD activity via UPR signalling, potentially serving as a protective response against Cyt-induced NMD component expression. Our findings highlight the central importance of RNA turnover in ß-cell responses to inflammatory stress.

TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression.

The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPADM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPADM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

Exploration of cell state heterogeneity using single-cell proteomics through sensitivity-tailored data-independent acquisition.

Single-cell resolution analysis of complex biological tissues is fundamental to capture cell-state heterogeneity and distinct cellular signaling patterns that remain obscured with population-based techniques. The limited amount of material encapsulated in a single cell however, raises significant technical challenges to molecular profiling. Due to extensive optimization efforts, single-cell proteomics by Mass Spectrometry (scp-MS) has emerged as a powerful tool to facilitate proteome profiling from ultra-low amounts of input, although further development is needed to realize its full potential. To this end, we carry out comprehensive analysis of orbitrap-based data-independent acquisition (DIA) for limited material proteomics. Notably, we find a fundamental difference between optimal DIA methods for high- and low-load samples. We further improve our low-input DIA method by relying on high-resolution MS1 quantification, thus enhancing sensitivity by more efficiently utilizing available mass analyzer time. With our ultra-low input tailored DIA method, we are able to accommodate long injection times and high resolution, while keeping the scan cycle time low enough to ensure robust quantification. Finally, we demonstrate the capability of our approach by profiling mouse embryonic stem cell culture conditions, showcasing heterogeneity in global proteomes and highlighting distinct differences in key metabolic enzyme expression in distinct cell subclusters.

Quadrivalent HPV vaccine effectiveness against anogenital warts: A registry-based study of 2,2 million individuals.

BACKGROUND: In 2009, Norway initiated routine quadrivalent HPV (qHPV) vaccination for girls at 12-13 years of age to protect against virus types causing cervical cancer, HPV16/18, and HPV6/11 which cause anogenital warts (AGW). We wanted to investigate qHPV vaccine effectiveness (VE) against AGW in females before and after first AGW episode and to assess the impact of female vaccination in males. MATERIALS AND METHODS: QHPV vaccination and AGW episodes were collected for the time period 2006-2016 for birth cohorts 1975-2003. Cox models were applied to age at first, as well as at second AGW episode. Finally, we estimated the impact of the female vaccination program on unvaccinated males. RESULTS: The VE against the first episode of AGW was strongly dependent on vaccination age, with hazard ratios (HRs) compared to unvaccinated individuals of 0.2, 0.2, 0.3, 0.5, 1.0, 1.3, and 2.7, for age groups of ⩽13, 14-15, 16-17, 18-19, 20-24, 25-29, and 30+ years at first vaccination, respectively. Among women who had suffered a first episode of AGW, subsequent qHPV vaccination did not protect against a second episode, with HRs of 0.8, 1.0, and 1.4, for age groups of ⩽17, 18-24, and 25+ years at first vaccination. A gradually decreasing AGW risk was seen in unvaccinated male cohorts neighboring the first routinely vaccinated female 1997 cohort. CONCLUSIONS: When administered before 14 years of age, qHPV vaccination reduced the probability of AGW about fivefold. The effect decreased sharply with vaccination age, and was not significant among women vaccinated after age 20 years. QHPV administered after the first AGW episode did not protect against a second AGW episode. Herd effects were indicated in unvaccinated males, as we observed a gradual decrease in AGW rates from the 1993 male birth cohort and onwards.

Unpacking the Lay Epidemiology of Cervical Cancer: A Focus Group Study on the Perceptions of Cervical Cancer and Its Prevention among Women Late for Screening in Norway.

Nonattendance for cervical cancer screening is often understood in terms of a lack of 'appropriate' or 'correct' knowledge about the risks and prevention of the disease. Few studies have explored how lay persons-the users themselves-interpret and contextualise scientific knowledge about cervical cancer. In this study, we address the following research question: How is the epidemiology of cervical cancer and its prevention discussed among women who are late for cervical cancer screening in Norway? We completed nine focus group interviews (FGIs) with 41 women who had postponed cervical screening. The analyses were both inductive and explorative, aiming to unpack the complexity of lay understandings of cervical cancer. Interactive associations expressed in the FGIs reflected multiple understandings of aetiology and risk factors, screening, and interpretations of responsibility for acquiring cervical cancer. The term 'candidacy' was employed to provide an enhanced understanding of lay reasoning about the explanations and predictions of cervical cancer, as reflected in the FGIs. Both interpretations of biomedical concepts and cultural values were used to negotiate acceptable and nuanced interpretations of candidacy for cervical cancer. Uncertainties about risk factors for acquiring cervical cancer was an important aspect of such negotiations. The study's findings provide an in-depth understanding of the contexts in which screening may be rendered less relevant or significant for maintaining health. Lay epidemiology should not be considered inappropriate knowledge but rather as a productive component when understanding health behaviours, such as screening attendance.

Factors associated with teenage pregnancy in the Scandinavian countries.

AIMS: Teenage pregnancy may have negative consequences for the mother and the infant. The aim of the study was to examine whether selected individual factors occurring early in life were associated with teenage pregnancy. METHODS: In a population-based, cross-sectional questionnaire study among 34,455 women from Denmark, Norway, and Sweden aged 20-45 years, who had first sexual intercourse (FSI) at age 13-19 years, we assessed the association between early smoking and drinking initiation (i.e., before the age of 13), contraceptive use at FSI, and teenage pregnancy. Log-linear binary regression models were fitted to estimate the relative risk (RR) with 95% confidence intervals (CIs) of teenage pregnancy according to the three exposure variables, overall and by age at FSI. Furthermore, the outcomes of the teenage pregnancies were examined according to age at FSI. RESULTS: Teenage pregnancy occurred in 11% of the population. Both early smoking initiation (RR: 1.6; 95% CI: 1.4-1.8), early drinking initiation (RR: 1.2; 95% CI: 1.0-1.4), and non-use of contraceptives at FSI (RR: 1.9; 95% CI: 1.8-2.0) were associated with teenage pregnancy. The associations for early smoking initiation and non-use of contraceptives remained when analyses were stratified by age at FSI. Almost 60% of all teenage pregnant women had an induced abortion and less than 30% gave birth. CONCLUSIONS: Individual factors, including early smoking and drinking initiation, and non-use of contraceptives at FSI, were associated with teenage pregnancy regardless of age at FSI. This emphasizes the necessity of focusing on early risk-taking behavior as a potential modifier to prevent teenage pregnancy.

Real-world effectiveness of HPV vaccination against cervical neoplasia among birth cohorts ineligible for routine vaccination.

Human papillomavirus (HPV) vaccine effectiveness may differ between settings. Here we present the first real-world effectiveness study of HPV vaccination on high-grade cervical lesions from Norway, among women who received HPV vaccine outside the routine program. We performed an observational study of all Norwegian women born 1975 to 1996 and retrieved individual data from nationwide registries on HPV vaccination status and incidence of histologically verified high-grade cervical neoplasia during 2006 to 2016. We estimated the incidence rate ratio (IRR) and 95% confidence intervals (CI) for vaccination vs no vaccination by Poisson regression stratified by age at vaccination <20 years and ≥20 years. The cohort consisted of 832 732 women, of which 46 381 (5.6%) received at least one dose of HPV vaccine by the end of 2016. The incidence rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increased with age regardless of vaccination status and was highest at age 25 to 29, at 637/100 000 among unvaccinated women, 487/100 000 among women vaccinated before age 20 and 831/100 000 among women vaccinated at age 20 or older. The adjusted IRR of CIN2+ between vaccinated and unvaccinated women was 0.62 (95% CI: 0.46-0.84) for women vaccinated below age 20, and 1.22 (95% CI: 1.03-1.43) for women vaccinated at age 20 or older. These findings indicate that HPV vaccination among women too old to be eligible for routine HPV vaccination is effective among women who are vaccinated below age 20 but may not have the desired impact among women who are vaccinated at age 20 or older.

Coverage of primary and booster vaccination against COVID-19 by socioeconomic level: A nationwide cross-sectional registry study.

High and equitable COVID-19 vaccination coverage is important for pandemic control and prevention of health inequity. However, little is known about socioeconomic correlates of booster vaccination coverage. In this cross-sectional study of all Norwegian adults in the national vaccination program (N = 4,190,655), we use individual-level registry data to examine coverage by levels of household income and education of primary (≥2 doses) and booster (≥3 doses) vaccination against COVID-19. We stratify the analyses by age groups with different booster recommendations and report relative risk ratios (RR) for vaccination by 25 August 2022. In the 18-44 y group, individuals with highest vs. lowest education had 94% vs. 79% primary coverage (adjusted RR (adjRR) 1.15, 95%CI 1.14-1.15) and 67% vs. 38% booster coverage (adjRR 1.55, 95% CI 1.55-1.56), while individuals with highest vs. lowest income had 94% vs. 81% primary coverage (adjRR 1.10, 95%CI 1.10-1.10) and 60% vs. 43% booster coverage (adjRR 1.23, 95%CI 1.22-1.24). In the ≥45 y group, individuals with highest vs. lowest education had 96% vs. 92% primary coverage (adjRR 1.02, 95%CI 1.02-1.02) and 88% vs. 80% booster coverage (adjRR 1.09, 95%CI 1.09-1.09), while individuals with highest vs. lowest income had 98% vs. 82% primary coverage (adjRR 1.16, 95%CI 1.16-1.16) and 92% vs. 64% booster coverage (adjRR 1.33, 95%CI 1.33-1.34). In conclusion, we document large socioeconomic inequalities in COVID-19 vaccination coverage, especially for booster vaccination, even though all vaccination was free-of-charge. The results highlight the need to tailor information and to target underserved groups for booster vaccination.

The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes.

Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.