Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia.

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.

Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster.

Mammalian sex determination is controlled by antagonistic gene cascades operating in embryonic undifferentiated gonads. The expression of the Y-linked gene SRY is sufficient to trigger the testicular pathway, whereas its absence in XX embryos leads to ovarian differentiation. Yet, the potential involvement of non-coding regulation in this process remains unclear. Here we show that the deletion of a single microRNA cluster, miR-17~92, induces complete primary male-to-female sex reversal in XY mice. Sry expression is delayed in XY knockout gonads, which develop as ovaries. Sertoli cell differentiation is reduced, delayed and unable to sustain testicular development. Pre-supporting cells in mutant gonads undergo a transient state of sex ambiguity which is subsequently resolved towards the ovarian fate. The miR-17~92 predicted target genes are upregulated, affecting the fine regulation of gene networks controlling gonad development. Thus, microRNAs emerge as key components for mammalian sex determination, controlling Sry expression timing and Sertoli cell differentiation.

The scene of lung pathology during PRRSV-1 infection.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important infectious diseases for the pig industry worldwide. The disease was firstly reported in 1987 and became endemic in many countries. Since then, outbreaks caused by strains of high virulence have been reported several times in Asia, America and Europe. Interstitial pneumonia, microscopically characterised by thickened alveolar septa, is the hallmark lesion of PRRS. However, suppurative bronchopneumonia and proliferative and necrotising pneumonia are also observed, particularly when a virulent strain is involved. This raises the question of whether the infection by certain strains results in an overstimulation of the proinflammatory response and whether there is some degree of correlation between the strain involved and a particular pattern of lung injury. Thus, it is of interest to know how the inflammatory response is modulated in these cases due to the interplay between virus and host factors. This review provides an overview of the macroscopic, microscopic, and molecular pathology of PRRSV-1 strains in the lung, emphasising the differences between strains of different virulence.

Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.

Staging amyloid-beta (Aß) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aß pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aß ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aß-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aß therapies.

Examining the influence of mental health and structural determinants of health on the stage of motivational readiness for health behaviour changes: A path analysis study.

This study explores the influence of mental health and structural determinants of health on motivational readiness for health behaviour change in 1462 Spanish primary healthcare users. Chi-square test and structural equation modelling were performed. Results showed that depression and anxiety were negatively associated with being in the action stages of motivational readiness for a healthy diet and physical activity. This association was statistically significant only for motivational readiness for a healthy diet and depression (ß=-0.076;p=0.046). Furthermore, women and workers were more likely to be in the action stages of motivational readiness for a healthy diet while older adults and adults with higher health-related quality of life were more likely to be in the action stages of motivational readiness for physical activity. The present study suggests that structural (being older, being a woman and being employed) and intermediary (suffering from depression and higher health-related quality of life) determinants of health influence motivational readiness for health behaviour changes.

Macrophage polarization in lymph node granulomas from cattle and pigs naturally infected with Mycobacterium tuberculosis complex.

Tuberculosis in animals is caused by members of the Mycobacterium tuberculosis complex (MTC), with the tuberculous granuloma being the main characteristic lesion. The macrophage is the main cell type involved in the development of the granuloma and presents a wide plasticity ranging from polarization to classically activated or pro-inflammatory macrophages (M1) or to alternatively activated or anti-inflammatory macrophages (M2). Thus, this study aimed to analyze macrophage polarization in granulomas from cattle and pig lymph nodes naturally infected with MTC. Tuberculous granulomas were microscopically categorized into four stages and a panel of myeloid cells (CD172a/calprotectin), M1 macrophage polarization (iNOS/CD68/CD107a), and M2 macrophage polarization (Arg1/CD163) markers were analyzed by immunohistochemistry. CD172a and calprotectin followed the same kinetics, having greater expression in late-stage granulomas in pigs. iNOS and CD68 had higher expression in cattle compared with pigs, and the expression was higher in early-stage granulomas. CD107a immunolabeling was only observed in porcine granulomas, with a higher expression in stage I granulomas. Arg1+ cells were significantly higher in pigs than in cattle, particularly in late-stage granulomas. Quantitative analysis of CD163+ cells showed similar kinetics in both species with a consistent frequency of immunolabeled cells throughout the different stages of the granuloma. Our results indicate that M1 macrophage polarization prevails in cattle during early-stage granulomas (stages I and II), whereas M2 phenotype is observed in later stages. Contrary, and mainly due to the expression of Arg1, M2 macrophage polarization is predominant in pigs in all granuloma stages.

Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes.

The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax.

Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma.

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

PURPOSE: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Blood Biomarkers of Alzheimer's Disease and Cognition: A Literature Review.

Recent advances in blood-based biomarkers of Alzheimer's Disease (AD) show great promise for clinical applications, offering a less invasive alternative to current cerebrospinal fluid (CSF) measures. However, the relationships between these biomarkers and specific cognitive functions, as well as their utility in predicting longitudinal cognitive decline, are not yet fully understood. This descriptive review surveys the literature from 2018 to 2023, focusing on the associations of amyloid-ß (Aß), Total Tau (t-Tau), Phosphorylated Tau (p-Tau), Neurofilament Light (NfL), and Glial Fibrillary Acidic Protein (GFAP) with cognitive measures. The reviewed studies are heterogeneous, varying in design and population (cognitively unimpaired, cognitively impaired, or mixed populations), and show results that are sometimes conflicting. Generally, cognition positively correlates with Aß levels, especially when evaluated through the Aß42/Aß40 ratio. In contrast, t-Tau, p-Tau, Nfl, and GFAP levels typically show a negative correlation with cognitive performance. While p-Tau measures generally exhibit stronger associations with cognitive functions compared to other biomarkers, no single blood marker has emerged as being predominantly linked to a specific cognitive domain. These findings contribute to our understanding of the complex relationship between blood biomarkers and cognitive performance and underscore their potential utility in clinical assessments of cognition.

Effectiveness of multiple health behavior change interventions in reducing symptoms of anxiety in the adult population: A systematic review and meta-analysis of randomized controlled trials.

There is limited evidence regarding the effectiveness of preventive interventions for anxiety disorders. We aim to test the effectiveness of multiple health behavior change (MHBC) interventions in the reduction of symptoms of anxiety in the adult population. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted by searching the most relevant databases and registry platforms in the area. Reference lists of included articles and relevant systematic reviews and meta-analyses of MHBC interventions that examined anxiety or depression as outcomes were also manually searched. To identify RCTs that evaluated preventive interventions, we excluded studies in which the target population included only patients meeting the diagnostic criteria for anxiety disorders. To pool results, the standardized mean difference (SMD) was calculated using the random effects model. Sensitivity, subgroup and meta-regression analyses were performed. Forty-six RCTs were included in the qualitative synthesis, and 34 RCTs were included in the meta-analysis. Thirty RCTs were focused on promoting healthy diet and physical activity, whereas the other 16 studies also focused on smoking cessation. The pooled SMD was small (-0.183; 95% CI -0.276 to -0.091) but significant (p < 0.001). The effect became non-significant when only studies with a low risk of bias were included. There was substantial and significant heterogeneity between the studies. There is currently insufficient evidence regarding the effectiveness of MHBC interventions to reduce symptoms of anxiety in the adult population.

Risk of cognitive decline progression is associated to increased blood-brain-barrier permeability: A longitudinal study in a memory unit clinical cohort.

INTRODUCTION: This study examined the relationship between blood-brain-barrier permeability (BBBp), measured by cerebrospinal fluid/serum albumin ratio (QAlb), and cognitive decline progression in a clinical cohort. METHODS: This prospective observational study included 334 participants from the BIODEGMAR cohort. Cognitive decline progression was defined as an increase in Global Deterioration Scale and/or Clinical Dementia Rating scores. Associations between BBBp, demographics, and clinical factors were explored. RESULTS: Male sex, diabetes mellitus, and cerebrovascular burden were associated with increased log-QAlb. Vascular cognitive impairment patients had the highest log-QAlb levels. Among the 273 participants with valid follow-up data, 154 (56.4%) showed cognitive decline progression. An 8% increase in the hazard of clinical worsening was observed for each 10% increase in log-QAlb. DISCUSSION: These results suggest that increased BBBp in individuals with cognitive decline may contribute to clinical worsening, pointing to potential targeted therapies. QAlb could be a useful biomarker for identifying patients with a worse prognosis.

Global prevalence of perinatal depression and anxiety during the COVID-19 pandemic: An umbrella review and meta-analytic synthesis.

INTRODUCTION: The prevalence of depression and anxiety symptoms in pregnant and postpartum women during the COVID-19 pandemic was assessed by several systematic reviews (SRs) and meta-analyses which provided contrasting and different results. We aimed to summarize the evidence relating to the global prevalence of anxiety and depression among pregnant and postpartum women during the COVID-19 pandemic. MATERIAL AND METHODS: An umbrella review of SRs and meta-analyses was performed. Searches were conducted in electronic databases up to April 2023. SRs and meta-analyses reporting the prevalence of perinatal anxiety and depression during the COVID-19 pandemic were selected for eligibility. Primary studies extracted from eligible meta-analyses were included in the quantitative synthesis. The research protocol was registered on PROSPERO (CRD42020173125). RESULTS: A total of 25 SRs (198 primary studies) and 12 meta-analyses (129 primary studies) were included in the qualitative and quantitative synthesis, respectively. Studies involved data from five continents and 45 countries. The pooled prevalence of antenatal and postpartum depression was 29% (n = 55; 95% CI: 25%-33%) and 26% (n = 54; 95% CI: 23%-30%), respectively. In the case of anxiety, the pooled antenatal and postnatal prevalence was 31% (n = 44; 95% CI: 26%-37%; n = 16; 95% CI: 24%-39%). Differences emerged between continents, with Africa having the highest prevalence of perinatal depression and Oceania and Europe having the highest prevalence of antenatal and postnatal anxiety. The prevalence also varied depending on the assessment tools, especially for antenatal anxiety. A medium-high quality of the studies was observed. One SR assessed strength-of-evidence, reporting very low strength. CONCLUSIONS: During the COVID-19 pandemic, depression and anxiety were common, affecting almost one in three perinatal women globally. A high heterogeneity and a risk of publication bias were found, partially due to the variety of assessment tools and cut-offs. The results may not be generalized to minorities. Studies on the prevalence of clinical diagnoses are needed. Based on our results it is not possible to firmly affirm that the COVID-19 pandemic was the main factor that directly increased perinatal depression and anxiety during the past few years. Future studies should study other factors' impact.

Perceptions and attitudes regarding delayed antibiotic prescription for respiratory tract infections: a qualitative study.

BACKGROUND: Antibiotics are overprescribed for respiratory tract infections (RTIs). However, the decision to prescribe is often complex. Delayed antibiotic prescription (DAP), a strategy designed to promote more rational antibiotic use, is still not widely used. The aim of this study was to explore perceptions and attitudes in primary care professionals, regarding antibiotic use and different DAP strategies for uncomplicated RTIs. METHODS: We conducted a qualitative study, using an inductive thematic approach to generate themes, based on focus group discussions and semi-structured interviews with professionals, recruited from 6 primary care centres (Barcelona metropolitan area, Spain). RESULTS: 26 professionals (25 family physicians and one nurse) were included in four focus group discussions and three semi-structured interviews. Participants commented that RTIs were a main reason for consultation, motivated often by patient anxiety and fear of possible complications, and this was associated with the patients' poor health-related education. Acknowledging inappropriate antibiotic use in the health system, participants attributed this, mainly to defensive medicine strategies. DAP was used when in doubt about the aetiology, and considering factors related to patient-physician interactions. The main perceived advantage of DAP was that it could reduce the need for additional visits, while the main disadvantage was uncertainty regarding proper use by the patient. CONCLUSIONS: DAP was used by participants in cases of doubt, in specific situations, and for specific patient profiles. Weak points were detected in our primary care system and its users that affect the proper use of both antibiotics and DAP, namely, time pressure on professionals, poor patient health-related education, and the lack of a patient-physician relationship in some scenarios.

IL-1ß-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs' genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs' differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1ß-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2 . This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.

Diagnostic performance of faecal and tissue multiplex qPCR IS900/F57 for the detection of Mycobacterium avium subspecies paratuberculosis in cattle.

Mycobacterium avium subspecies paratuberculosis (MAP) is responsible for bovine-paratuberculosis (bPTB), which causes high production losses in cattle. A cross-sectional study was conducted in 228 cattle to evaluate the validity and diagnostic utility of a multiplex real-time PCR (qPCR) on faecal and intestinal samples [ileocaecal valve (ICV) and ileocaecal lymph nodes (ICLN)], using intestinal tissue culture as a reference test. Based on the sensitivity, specificity, and likelihood ratios (LR) obtained, the diagnostic value of faecal qPCR for confirming MAP infection was moderate (sensitivity 50.3%, specificity 93.5%, positive LR 7.8), and low to rule it out (negative LR 0.5). In areas with a prevalence of >23% the credibility of positive results was higher than 70%. In the case of negative results, their credibility was higher than 90% in herds with an infection rate below 19%, so faecal qPCR would be very useful in these areas to certify the absence of infection. For post-mortem diagnosis, qPCR on ICV samples showed good diagnostic accuracy to confirm the disease (sensitivity 71.7%, specificity 93.3%, positive LR 10.8), with a credibility higher than 70% in animals from areas or herds with a prevalence of infection greater than or equal to 18%. The best strategy to rule out the disease was the parallel combination of both tissues (ICV + ICLN) (sensitivity 81.3%, specificity 89.5%, negative LR 0.2) with a credibility of over 95% in animals from areas with an infection prevalence of 0-20%. Faecal and tissues qPCR techniques can be used to monitor bPTB, the interpretation of results, according to epidemiological situation of the herd or area, are shown.

Impact of supplementation with dihydroxylated vitamin D3 on performance parameters and gut health in weaned Iberian piglets under indoor/outdoor conditions.

BACKGROUND: Vitamin D may improve innate antimicrobial response and the integrity of the intestinal mucosal barrier representing an alternative to antibiotics for improving pig health. Therefore, benefits of dietary supplementation with a product based on vitamin D3 metabolite-rich plant extracts were assessed in 252 purebred Iberian piglets for a period of 60 days. The study group received 1,25 dihydroxyvitamin D (1,25(OH)2D) (100 ppm) in the conventional feed, which already included vitamin D (2000 IU in the starter and 1000 IU in the adaptation diets, respectively). Average daily gain (ADG), feed conversion ratio (FCR) and coefficient of variation of body weight (CV-BW) were assessed along the study. Blood samples, from 18 animals of the study group and 14 animals of the control group, were collected at selected time points to determine white blood cell count, concentration of vitamin D3 and its metabolites, and IgA and IgG in serum. Histopathology, morphometry, and immunohistochemistry (IgA and FoxP3) from small intestine samples were performed on days 30 and 60 of the study from 3 animals per group and time point. RESULTS: The ADG (493 vs 444 g/day) and FCR (2.3 vs 3.02) showed an improved performance in the supplemented animals. Moreover, the lower CV-BW indicated a greater homogeneity in the treated batches (13.17 vs 26.23%). Furthermore, a mild increase of IgA and in the number of regulatory T cells in the small intestine were observed in treated pigs. CONCLUSIONS: These results highlight the benefits of this supplementation and encourage to develop further studies along other production stages.

Role of personal aptitudes as determinants of incident morbidity, lifestyles, quality of life, use of the health services and mortality (DESVELA cohort): qualitative study protocol for a prospective cohort study in a hybrid analysis.

Introduction: Maintaining or acquiring healthier health-oriented behaviours and promoting physical and mental health amongst the Spanish population is a significant challenge for Primary Health Care. Although the role of personal aptitudes (characteristics of each individual) in influencing health behaviours is not yet clear, these factors, in conjunction with social determinants such as gender and social class, can create axes of social inequity that affect individuals' opportunities to engage in health-oriented behaviours. Additionally, lack of access to health-related resources and opportunities can further exacerbate the issue for individuals with healthy personal aptitudes. Therefore, it is crucial to investigate the relationship between personal aptitudes and health behaviours, as well as their impact on health equity. Objectives: This paper outlines the development, design and rationale of a descriptive qualitative study that explores in a novel way the views and experiences on the relationship between personal aptitudes (activation, health literacy and personality traits) and their perception of health, health-oriented behaviours, quality of life and current health status. Method and analysis: This qualitative research is carried out from a phenomenological perspective. Participants will be between 35 and 74 years of age, will be recruited in Primary Health Care Centres throughout Spain from a more extensive study called DESVELA Cohort. Theoretical sampling will be carried out. Data will be collected through video and audio recording of 16 focus groups in total, which are planned to be held in 8 different Autonomous Communities, and finally transcribed for a triangulated thematic analysis supported by the Atlas-ti program. Discussion: We consider it essential to understand the interaction between health-related behaviours as predictors of lifestyles in the population, so this study will delve into a subset of issues related to personality traits, activation and health literacy.Clinical trial registration: ClinicalTrials.gov, identifier NCT04386135.

Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance in RAS -mutated chronic myelomonocytic leukemia.

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Using single-cell, multi-omics technologies, we sought to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We found that RAS pathway mutations induced the transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs), which underwent proliferation and monocytic differentiation in response to cell-intrinsic and -extrinsic inflammatory signaling that also impaired immune cells' functions. HSPCs expanded at disease progression and relied on the NF- K B pathway effector MCL1 to maintain their survival, which explains why patients with RAS pathway- mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients with RAS pathway- mutated CMML.