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Airway basal cells are crucial for regeneration of the human lung airway epithelium and are believed to be important contributors to chronic obstructive pulmonary disease (COPD) and other lung disorders. To reveal how basal cells contribute to disease and to discover novel therapeutic targets, these basal cells need to be further characterized. In this study, we optimized a flow cytometry-based cell sorting protocol for primary human airway basal cells dependent on cell size and NGFR (nerve-growth factor receptor) expression. The basal cell population was found to be molecularly and functionally heterogeneous, in contrast to cultured basal cells. In addition, significant differences were found, such as KRT14 expression exclusively existing in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single-cell RNA sequencing on primary basal cells from healthy donors and patients with Global Initiative for Chronic Obstructive Lung Disease stage IV COPD, the gene expression revealed a continuum ranging from healthy basal cell signatures to diseased basal cell phenotypes. We identified several upregulated genes that may indicate COPD, such as stress response-related genes GADD45B and AHSA1, together with with genes involved in the response to hypoxia, such as CITED2 and SOD1. Taken together, the presence of healthy basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms as well as for developing future cell-based therapies in the human lung. !! [ABSTRACT FROM AUTHOR]

The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1 IS (%) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis. The patients with treatment failure after 12 months of therapy had a markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multiomic feature landscape enabled visualization of the primitive fraction as a mixture of molecularly distinct BCR::ABL1 + LSCs and BCR::ABL1 - hematopoietic stem cells (HSCs) in variable ratio across patients, and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers. We for the first time show that BCR::ABL1 + LSCs and BCR::ABL1 - HSCs can be distinctly separated as CD26 + CD35 - and CD26 - CD35 + , respectively. In addition, we found the ratio of LSC/HSC to be higher in patients with prospective treatment failure compared to optimal responders, at diagnosis as well as following 3 months of TKI therapy. Collectively, this data builds a framework for understanding therapy response and adapting treatment by devising strategies to extinguish or suppress TKI-insensitive LSCs., Competing Interests: RW, LG, FS, MS, SS, RT No competing interests declared, PD, GK Is a board member and has equity in Nygen Analytics AB, HH Received honoraria from Pfizer, Novartis, BMS, and Incyte, SM Received honoraria and research funding from BMS, research funding from Novartis, Janpix, and honoraria from Dren Bio, JR Received honoraria and research funding from Novartis and Bristol-Myers Squibb (BMS) and honoraria from Ariad, (© 2023, Warfvinge et al.)

Temporal trends for concentrations of mercury (Hg), lead (Pb) and cadmium (Cd) were evaluated from year 2000-2020 in 20 (Hg), 23 (Pb) and 11 (Cd) watercourses in remote forest catchments in Europe. Decreasing trends were observed in 15% (Hg), 39% (Pb) and 45% (Cd) of the watercourses during the period of evaluation. Decreasing trends were mainly observed between 2000 and 2005 for Hg and between 2000 and 2015 for Pb and Cd. For the last five years of the studied time period (2015-2020), more watercourses showed significant increasing, rather than decreasing Hg, Pb and Cd trends. This was interpreted as a legacy effect of metals still retained in catchment soils. The overall negative trends during the earlier part of the study period were likely driven by declining deposition of metals over Europe, especially for Pb and Cd. Other changes related to metal transport and chemistry may have contributed to the observed trends as well, including recovery from acidification and the ongoing browning of surface waters at northern latitudes. Here we found that organic carbon could explain the seasonal variation in Hg and Pb, but was not related the interannual trends. This study highlights the need for long-term monitoring and robust statistical methods that can detect multidirectional, long-term change in water chemistry., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR 15 N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time scales, along with the assessment of conformational populations by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, put the side chain of residue W580 in an inward position, shedding light at potential mechanisms underlying the allosteric regulation of this enzyme., (© 2024. The Author(s).)

The MUC2 mucin protects the colonic epithelium by a two-layered mucus with an inner attached bacteria-free layer and an outer layer harboring commensal bacteria. CysD domains are 100 amino-acid-long sequences containing 10 cysteines that separate highly O-glycosylated proline, threonine, serine (PTS) regions in mucins. The structure of the second CysD, CysD2, of MUC2 is now solved by nuclear magnetic resonance. CysD2 shows a stable stalk region predicted to be partly covered by adjacent O-glycans attached to neighboring PTS sequences, whereas the CysD2 tip with three flexible loops is suggested to be well exposed. It shows transient dimer interactions at acidic pH, weakened at physiological pH. This transient interaction can be stabilized in vitro and in vivo by transglutaminase 3-catalyzed isopeptide bonds, preferring a specific glutamine residue on one flexible loop. This covalent dimer is modeled suggesting that CysD domains act as connecting hubs for covalent stabilization of mucins to form a protective mucus., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Immunological control of residual leukemia cells is thought to occur in patients with chronic myeloid leukemia (CML) that maintain treatment-free remission (TFR) following tyrosine kinase inhibitor (TKI) discontinuation. To study this, we analyzed 55 single-cell RNA and T cell receptor (TCR) sequenced samples (scRNA+TCRαβ-seq) from patients with CML (n = 13, N = 25), other cancers (n = 28), and healthy (n = 7). The high number and active phenotype of natural killer (NK) cells in CML separated them from healthy and other cancers. Most NK cells in CML belonged to the active CD56 dim cluster with high expression of GZMA/B, PRF1, CCL3/4, and IFNG, with interactions with leukemic cells via inhibitory LGALS9-TIM3 and PVR-TIGIT interactions. Accordingly, upregulation of LGALS9 was observed in CML target cells and TIM3 in NK cells when co-cultured together. Additionally, we created a classifier to identify TCRs targeting leukemia-associated antigen PR1 and quantified anti-PR1 T cells in 90 CML and 786 healthy TCRβ-sequenced samples. Anti-PR1 T cells were more prevalent in CML, enriched in bone marrow samples, and enriched in the mature, cytotoxic CD8 + T EMRA cluster, especially in a patient maintaining TFR. Our results highlight the role of NK cells and anti-PR1 T cells in anti-leukemic immune responses in CML., (© 2023. The Author(s).)

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice., (© 2023. The Author(s).)

Background: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS)., Objective: Further characterize efficacy and safety of ofatumumab in RMS., Methods: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021., Results: In the efficacy set ( n  = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04-0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter "no evidence of disease activity" criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set ( n  = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified., Conclusion: Ofatumumab has a favorable longer-term benefit-risk profile in RMS., Trial Registry: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All support for the present manuscript (e.g. funding, provision of study materials, medical writing, article processing charges) and the studies were sponsored and funded by Novartis Pharma AG, Basel, Switzerland. Novartis Pharma AG supported the development of this manuscript, provided data analyses according to the direction of the authors, and provided funding for medical writing support. Open access fee was paid by Novartis. Medical writing support for the development of this publication, under the direction of the authors, was provided by James Currie (BSc, Hons; PhD.), Laura Crocker (BMedSci, Hons), and Philippa Lloyd (BSc, Hons) of Ashfield MedComms, an Inizio company, and was funded by Novartis Pharma AG. Stephen L Hauser currently serves on the scientific advisory board of ACCURE, Alector, Annexon, board of directors of Neurona, and has previously consulted for BD, Moderna, and NGM Bio. Dr Hauser also has received travel reimbursement and writing support from F. Hoffmann-La Roche and Novartis AG for anti-CD20-therapy-related meetings and presentations. Grants: NIH/NINDS (R35NS111644) and Valhalla Foundation; within the past 36 months, no longer active: National Multiple Sclerosis Society (RR 2005-A-13). Ronald Zielman is a full-time employee of Novartis. Ayan Das Gupta is a paid and permanent employee of Novartis. Jing Xi is an employee of Novartis. Dee Stoneman is a full-time employee of Novartis. Goeril Karlsson is a full-time salaried employee of Novartis. Derrick Robertson declares grants or contracts from Anokion, Atara Biotherapeutics, Biogen, GW Pharmaceuticals, Novartis, PRIME CME, TG Therapeutics, CorEvitas, EMD Serono, Genentech, Janssen, PCORI and Sanofi; consulting fees from Biogen, Genentech, EMD Serono, Janssen, Bristol Myers Squibb, Horizon, Novartis, Sanofi, TG Therapeutics, Alexion, Greenwich Biosciences and Mallinckrodt; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, EMD Serono, Genentech, TG Therapeutics, Bristol Myers Squibb, Janssen, PRIME CME, Sanofi, Alexion and Horizon. Jeffrey A Cohen declares consulting fees from Biogen, Convelo, EMD Serono, Gaossamer Gio, Mylan and PSA; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for ACTRIMS; other financial or non-financial interests for Sage—serving as an Editor of Mult Scler J. Ludwig Kappos declares grants or contracts from any entity (payments made to institution) from Novartis, Roche, and Innosuisse; consulting fees (payments made to institution) from AurigaVision AG, Bayer AG, df-mp Molnia & Pohlman, Genentech, Glaxo Smith Kline, Janssen LLC, Japan Tobacco Inc., Merck, Novartis, Roche, Senda Biosciences Inc., Shionogi BV, Wellmera AG; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (payments made to institution) from BMS, Celgene, Janssen Pharmaceuticals, Merck, Novartis and Roche; support for attending meetings and/or travel (payments made to institution) from MH Consulting, Österreichische Gesellschaft für Neurologie, Novartis Biocieˆncias S.A. and Eli Lilly; participation on a Data Safety Monitoring Board or Advisory Board (AB, payments made to institution) from Actelion, Merck Healthcare KGaA, Novartis, Roche, Sanofi and TG Therapeutics and (DSMB, payments made to institution) from Minoryx Therapeutics S.L. and Santhera Pharmaceuticals; leadership or fiduciary role in other board, society, committee or advocacy group paid or unpaid from Neurostatus-UHB AG—Supervisory Board (unpaid), payment to institution; (charitable) Foundation Clinical Neuroimmunology and Neuroscience Basel (“RC2NB”)—CEO (employment by University Hospital Basel); MAGNBIMS Steering Committee, EUROPEAN CHARCOT FOUNDATION (Board membership)—no payment.

Knowledge of human fetal blood development and how it differs from adult blood is highly relevant to our understanding of congenital blood and immune disorders and childhood leukemia, of which the latter can originate in utero. Blood formation occurs in waves that overlap in time and space, adding to heterogeneity, which necessitates single-cell approaches. Here, a combined single-cell immunophenotypic and transcriptional map of first trimester primitive blood development is presented. Using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), the molecular profile of established immunophenotype-gated progenitors was analyzed in the fetal liver (FL). Classical markers for hematopoietic stem cells (HSCs), such as CD90 and CD49F, were largely preserved, whereas CD135 (FLT3) and CD123 (IL3R) had a ubiquitous expression pattern capturing heterogenous populations. Direct molecular comparison with an adult bone marrow data set revealed that the HSC state was less frequent in FL, whereas cells with a lymphomyeloid signature were more abundant. An erythromyeloid-primed multipotent progenitor cluster was identified, potentially representing a transient, fetal-specific population. Furthermore, differentially expressed genes between fetal and adult counterparts were specifically analyzed, and a fetal core signature was identified. The core gene set could separate subgroups of acute lymphoblastic leukemia by age, suggesting that a fetal program may be partially retained in specific subgroups of pediatric leukemia. Our detailed single-cell map presented herein emphasizes molecular and immunophenotypic differences between fetal and adult blood cells, which are of significance for future studies of pediatric leukemia and blood development in general., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Siponimod, a potent and selective sphingosine-1-phosphate (S1P 1,5 ) agonist, is the only therapeutic agent that has shown efficacy against disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P 1,3,45 agonist, failed to show efficacy against disability progression in PPMS. Differentiating siponimod from fingolimod at the level of their central effects is believed to be the key to a better understanding of the underlying characteristics that could make siponimod uniquely efficacious in progressive MS (PMS)., Methods: Here, we compared the central vs. peripheral dose-dependent drug exposures for siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE)., Results: Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady-state drug blood levels, with a central nervous system (CNS)/blood drug-exposure ratio ( CNS/blood DER) of ~ 6 in both healthy and EAE mice. In contrast, fingolimod treatments achieved dose-proportional increases in fingolimod and fingolimod-phosphate blood levels, with respective CNS/blood DER that were markedly increased (≥ threefold) in EAE vs. healthy mice., Conclusion: If proven to have translational value, these observations would suggest that CNS/blood DER may be a key differentiator for siponimod over fingolimod for clinical efficacy in PMS., (© 2023. The Author(s).)

Objective: To explore the care experiences of lesbian, bisexual, transgender, and queer (LBTQ) people during births where complications have arisen., Design: Data were collected through semi-structured interviews with self-identified LBTQ people who had experienced obstetrical and/or neonatal complications., Setting: Interviews were conducted in Sweden., Participants: A total of 22 self-identified LBTQ people participated. 12 had experienced birth complications as the birth parent and ten as the non-birth parent., Findings: Most participants had felt invalidated as an LBTQ family. Separation of the family due to complications elevated the number of hetero/cisnormative assumptions, as new encounters with healthcare professionals increased. Dealing with normative assumptions was particularly difficult in stressful and vulnerable situations. A majority of the birth parents experienced disrespectful treatment from healthcare professionals that violated their bodily integrity. Most participants experienced lack of vital information and emotional support, and expressed that the LBTQ identity made it harder to ask for help., Conclusions: Disrespectful treatment and deficiencies in care contributed to negative experiences when complications arose during birth. Trusting care relationships are important to protect the birth experience in case of complications. Validation of the LBTQ identity and access to emotional support for both birth and non-birth parents are crucial for preventing negative birth experiences., Implications for Practice: To reduce minority stress and create conditions for a trusting relationship, healthcare professionals should specifically validate the LBTQ identity, strive for continuity of carer and zero separation of the LBTQ family. Healthcare professionals should make extensive efforts to transfer LBTQ related information between wards., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aging negatively affects hematopoiesis, with consequences for immunity and acquired blood cell disorders. Although impairments in hematopoietic stem cell (HSC) function contribute to this, the in vivo dynamics of such changes remain obscure. Here, we integrate extensive longitudinal functional assessments of HSC-specific lineage tracing with single-cell transcriptome and epitope profiling. In contrast to recent suggestions from single-cell RNA sequencing alone, our data favor a defined structure of HSC/progenitor differentiation that deviates substantially from HSC-derived hematopoiesis following transplantation. Native age-dependent attrition in HSC differentiation manifests as drastically reduced lymphoid output through an early lymphoid-primed progenitor (MPP Ly-I). While in vitro activation fails to rescue lymphoid differentiation from most aged HSCs, robust lymphopoiesis can be achieved by culturing elevated numbers of candidate HSCs. Therefore, our data position rare chronologically aged HSC clones, fully competent at producing lymphoid offspring, as a prime target for approaches aimed to improve lymphopoiesis in the elderly., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Here we describe an in vitro co-culture system that can differentiate hematopoietic progenitor populations to all major hematopoietic lineages at clonal level. We present both a sensitive single-cell switch-culture system as well as a less laborious alternative barcoding protocol more convenient for larger cell numbers. Importantly, generation of all lineages from single long-term hematopoietic stem cells are described, following 21 days of culture. This protocol represents an efficient tool for validation experiments for single-cell genomics data. For complete details on the use and execution of this protocol, please refer to Safi et al. (2022). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Hematopoiesis is regulated by the bone marrow (BM) stroma. However, cellular identities and functions of the different BM stromal elements in humans remain poorly defined. Based on single-cell RNA sequencing (scRNAseq), we systematically characterized the human non-hematopoietic BM stromal compartment and we investigated stromal cell regulation principles based on the RNA velocity analysis using scVelo and studied the interactions between the human BM stromal cells and hematopoietic cells based on ligand-receptor (LR) expression using CellPhoneDB. scRNAseq led to the identification of six transcriptionally and functionally distinct stromal cell populations. Stromal cell differentiation hierarchy was recapitulated based on RNA velocity analysis and in vitro proliferation capacities and differentiation potentials. Potential key factors that might govern the transition from stem and progenitor cells to fate-committed cells were identified. In situ localization analysis demonstrated that different stromal cells were localized in different niches in the bone marrow. In silico cell-cell communication analysis further predicted that different stromal cell types might regulate hematopoiesis through distinct mechanisms. These findings provide the basis for a comprehensive understanding of the cellular complexity of the human BM microenvironment and the intricate stroma-hematopoiesis crosstalk mechanisms, thus refining our current view on human hematopoietic niche organization., Competing Interests: HL, SB, PD, GK, SL, SS No competing interests declared, (© 2023, Li et al.)

Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSC resulted in a significantly reduced regenerative capacity of HSC in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSC (as compared to wild-type HSC) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of adult HSC and HSC quiescence.