Transcriptional Basis of Mouse and Human Dendritic Cell Heterogeneity.

Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.

Auditory hair cells and spiral ganglion neurons regenerate synapses with refined release properties in vitro.

Ribbon synapses between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) in the inner ear are damaged by noise trauma and with aging, causing "synaptopathy" and hearing loss. Cocultures of neonatal denervated organs of Corti and newly introduced SGNs have been developed to find strategies for improving IHC synapse regeneration, but evidence of the physiological normality of regenerated synapses is missing. This study utilizes IHC optogenetic stimulation and SGN recordings, showing that, when P3-5 denervated organs of Corti are cocultured with SGNs, newly formed IHC/SGN synapses are indeed functional, exhibiting glutamatergic excitatory postsynaptic currents. When using older organs of Corti at P10-11, synaptic activity probed by deconvolution showed more mature release properties, closer to the specialized mode of IHC synaptic transmission crucial for coding the sound signal. This functional assessment of newly formed IHC synapses developed here, provides a powerful tool for testing approaches to improve synapse regeneration.

Molecular signatures define subtypes of auditory afferents with distinct peripheral projection patterns and physiological properties.

Type I spiral ganglion neurons (SGNs) are the auditory afferents that transmit sound information from cochlear inner hair cells (IHCs) to the brainstem. These afferents consist of physiological subtypes that differ in their spontaneous firing rate (SR), activation threshold, and dynamic range and have been described as low, medium, and high SR fibers. Lately, single-cell RNA sequencing experiments have revealed three molecularly defined type I SGN subtypes. The extent to which physiological type I SGN subtypes correspond to molecularly defined subtypes is unclear. To address this question, we have generated mouse lines expressing CreERT2 in SGN subtypes that allow for a physiological assessment of molecular subtypes. We show that Lypd1-CreERT2 expressing SGNs represent a well-defined group of neurons that preferentially innervate the IHC modiolar side and exhibit a narrow range of low SRs. In contrast, Calb2-CreERT2 expressing SGNs preferentially innervate the IHC pillar side and exhibit a wider range of SRs, thus suggesting that a strict stratification of all SGNs into three molecular subclasses is not obvious, at least not with the CreERT2 tools used here. Genetically marked neuronal subtypes refine their innervation specificity onto IHCs postnatally during the time when activity is required to refine their molecular phenotype. Type I SGNs thus consist of genetically defined subtypes with distinct physiological properties and innervation patterns. The molecular subtype-specific lines characterized here will provide important tools for investigating the role of the physiologically distinct type I SGNs in encoding sound signals.

Liver sinusoidal endothelial cells induce BMP6 expression in response to non-transferrin-bound iron.

Homeostatic adaptation to systemic iron overload involves transcriptional induction of bone morphogenetic protein 6 (BMP6) in liver sinusoidal endothelial cells (LSECs). BMP6 is then secreted to activate signaling of the iron hormone hepcidin (HAMP) in neighboring hepatocytes. To explore the mechanism of iron sensing by LSECs, we generated TfrcTek-Cre mice with endothelial cell-specific ablation of transferrin receptor 1 (Tfr1). We also used control Tfrcfl/fl mice to characterize the LSEC-specific molecular responses to iron using single-cell transcriptomics. TfrcTek-Cre animals tended to have modestly increased liver iron content (LIC) compared with Tfrcfl/fl controls but expressed physiological Bmp6 and Hamp messenger RNA (mRNA). Despite a transient inability to upregulate Bmp6, they eventually respond to iron challenges with Bmp6 and Hamp induction, yet occasionally to levels slightly lower relative to LIC. High dietary iron intake triggered the accumulation of serum nontransferrin bound iron (NTBI), which significantly correlated with liver Bmp6 and Hamp mRNA levels and elicited more profound alterations in the LSEC transcriptome than holo-transferrin injection. This culminated in the robust induction of Bmp6 and other nuclear factor erythroid 2-related factor 2 (Nrf2) target genes, as well as Myc target genes involved in ribosomal biogenesis and protein synthesis. LSECs and midzonal hepatocytes were the most responsive liver cells to iron challenges and exhibited the highest expression of Bmp6 and Hamp mRNAs, respectively. Our data suggest that during systemic iron overload, LSECs internalize NTBI, which promotes oxidative stress and thereby transcriptionally induces Bmp6 via Nrf2. Tfr1 appears to contribute to iron sensing by LSECs, mostly under low iron conditions.

Pediatric acute promyelocytic leukemia and Fanconi anemia: Case report and literature review.

Acute promyelocytic leukemia (APL) represents 5%-10% of childhood acute myeloid leukemia (AML) and is the most curable subtype of AML. Fanconi anemia (FA) is one of the most common inherited bone marrow failure syndromes caused by biallelic pathogenic variants (PV) in specific DNA-repair genes. Biallelic PVs in FANCD1/BRCA2 (FA-D1) account for 3% of FA and are associated with early-onset leukemia and a high risk of solid tumors. We report a 4 year-old boy from non-consanguineous parents diagnosed with standard risk APL. This child had café-au-lait spots and an extra thumb remnant. Genomic sequencing revealed two PV in FANCD1/BRCA2 confirming a diagnosis of FA-D1. Chromosomal breakage studies were compatible with FA. Each parent carried one variant and had no personal history of cancer. Morphological then molecular remissions were achieved with all-trans retinoic acid and Arsenic trioxide. This patient underwent haploidentical stem cell transplant. In addition to our patient, a literature search revealed four additional patients with APL/FA, with a total of three patients with FA-D1. This raises the possibility of an association between such rare disorders. Practical management of APL in the setting of FA-D1 is discussed with an overview of current evidence and knowledge gaps.

Cluster B personality disorders and psychotropic medications: a focused analysis of trends and patterns across sex and age groups.

PURPOSE: This study investigated sex and age differences in patterns of psychotropic medication use before and after the initial diagnosis of Cluster B personality disorders (PDs) and analyzed trends over time. METHODS: Analyzing data from the Quebec Integrated Chronic Disease Surveillance System for individuals newly diagnosed with Cluster B PD (≥ 14 years) between 2002 and 2018 and under the provincial public drug plan, we calculated yearly and monthly proportions of individuals exposed to psychotropic medications during the year before and after their diagnosis by sex and age. Robust Poisson regression models assessed the association between sex and exposure to psychotropic medications after the diagnosis of Cluster B PD. RESULTS: Among 87,778 individuals with a first Cluster B PD diagnosis (mean age: 44.5 years; 57.5% women), the proportion of users increased post-diagnosis. Notably, after diagnosis, females were more likely to receive psychiatric medications (between 78.9% and 83.7% during the study period vs. 72.8% and 76.8%). Males were less likely than females to receive antidepressants (adjusted prevalence ratio (aPR): 0.83; 99% confidence interval (CI): 0.82-0.85) and anxiolytics (aPR: 0.86; 99%CI: 0.84-0.88), whereas they had higher exposure to antipsychotics (aPR: 1.04; 99%CI: 1.02-1.06) and ADHD medications (aPR: 1.14; 99%CI: 1.07-1.2). Age-specific trends showed increased ADHD medication use among younger patients (14-24 years), and anxiolytic use predominated in those aged ≥ 65 years. CONCLUSIONS: Psychotropic medication use was high among Cluster B PD patients, with differences in medication classes according to age and sex. The marked sex and age differences in psychotropic medication use among Cluster B PD patients underscore the need for a sex-sensitive and age-specific approach in psychiatric care.

High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML.

RUNX1 is mutated in ∼10% of adult acute myeloid leukemia (AML). Although most RUNX1 mutations in this disease are believed to be acquired, they can also be germline. Indeed, germline RUNX1 mutations result in the well-described autosomal-dominant familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD, FPD/AML, FPDMM); ∼44% of affected individuals progress to AML or myelodysplastic syndromes. Using the Leucegene RUNX1 AML patient group, we sought to investigate the proportion of germline vs acquired RUNX1 mutations in this cohort. Our results showed that 30% of RUNX1 mutations in our AML cohort are germline. Molecular profiling revealed higher frequencies of NRAS mutations and other mutations known to activate various signaling pathways in these patients with RUNX1 germline-mutated AML. Moreover, 2 patients (mother and son) had co-occurrence of RUNX1 and CEBPA germline mutations, with variable AML disease onset at 59 and 27 years, respectively. Together, these data suggest a higher than anticipated frequency of germline RUNX1 mutations in the Leucegene cohort and further highlight the importance of testing for RUNX1 mutations in instances in which allogeneic stem cell transplantation using a related donor is envisioned.

Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML.

FLT3, DNMT3A, and NPM1 are the most frequently mutated genes in cytogenetically normal acute myeloid leukemia (AML), but little is known about how these mutations synergize upon cooccurrence. Here we show that triple-mutated AML is characterized by high leukemia stem cell (LSC) frequency, an aberrant leukemia-specific GPR56 highCD34low immunophenotype, and synergistic upregulation of Hepatic Leukemia Factor (HLF). Cell sorting based on the LSC marker GPR56 allowed isolation of triple-mutated from DNMT3A/NPM1 double-mutated subclones. Moreover, in DNMT3A R882-mutated patients, CpG hypomethylation at the HLF transcription start site correlated with high HLF mRNA expression, which was itself associated with poor survival. Loss of HLF via CRISPR/Cas9 significantly reduced the CD34+GPR56+ LSC compartment of primary human triple-mutated AML cells in serial xenotransplantation assays. HLF knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when reintroduced in culture. RNA sequencing of primary human triple-mutated AML cells after shRNA-mediated HLF knockdown revealed the NOTCH target Hairy and Enhancer of Split 1 (HES1) and the cyclin-dependent kinase inhibitor CDKN1C/p57 as novel targets of HLF, potentially mediating these effects. Overall, our data establish HLF as a novel LSC regulator in this genetically defined high-risk AML subgroup.

H3K27M/I mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations.

Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of H3K27M mutations in pediatric glioblastoma and their well-established impact on global histone H3 lysine 27 di- and trimethylation (H3K27me2/3), the relevance of these mutations has not been studied in acute myeloid leukemia (AML). Here, we report the first identification of H3K27M and H3K27I mutations in patients with AML. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they are associated with common aberrations in the RUNX1 gene. We demonstrate that H3K27I/M mutations are strong disease accelerators in a RUNX1-RUNX1T1 AML mouse model, suggesting that H3K27me2/3 has an important and selective leukemia-suppressive activity in this genetic context.

MiSTIC, an integrated platform for the analysis of heterogeneity in large tumour transcriptome datasets.

Genome-wide transcriptome profiling has enabled non-supervised classification of tumours, revealing different sub-groups characterized by specific gene expression features. However, the biological significance of these subtypes remains for the most part unclear. We describe herein an interactive platform, Minimum Spanning Trees Inferred Clustering (MiSTIC), that integrates the direct visualization and comparison of the gene correlation structure between datasets, the analysis of the molecular causes underlying co-variations in gene expression in cancer samples, and the clinical annotation of tumour sets defined by the combined expression of selected biomarkers. We have used MiSTIC to highlight the roles of specific transcription factors in breast cancer subtype specification, to compare the aspects of tumour heterogeneity targeted by different prognostic signatures, and to highlight biomarker interactions in AML. A version of MiSTIC preloaded with datasets described herein can be accessed through a public web server (http://mistic.iric.ca); in addition, the MiSTIC software package can be obtained (github.com/iric-soft/MiSTIC) for local use with personalized datasets.

Different CaV1.3 Channel Isoforms Control Distinct Components of the Synaptic Vesicle Cycle in Auditory Inner Hair Cells.

The mechanisms orchestrating transient and sustained exocytosis in auditory inner hair cells (IHCs) remain largely unknown. These exocytotic responses are believed to mobilize sequentially a readily releasable pool of vesicles (RRP) underneath the synaptic ribbons and a slowly releasable pool of vesicles (SRP) at farther distance from them. They are both governed by Cav1.3 channels and require otoferlin as Ca2+ sensor, but whether they use the same Cav1.3 isoforms is still unknown. Using whole-cell patch-clamp recordings in posthearing mice, we show that only a proportion (∼25%) of the total Ca2+ current in IHCs displaying fast inactivation and resistance to 20 µm nifedipine, a l-type Ca2+ channel blocker, is sufficient to trigger RRP but not SRP exocytosis. This Ca2+ current is likely conducted by short C-terminal isoforms of Cav1.3 channels, notably Cav1.342A and Cav1.343S, because their mRNA is highly expressed in wild-type IHCs but poorly expressed in Otof-/- IHCs, the latter having Ca2+ currents with considerably reduced inactivation. Nifedipine-resistant RRP exocytosis was poorly affected by 5 mm intracellular EGTA, suggesting that the Cav1.3 short isoforms are closely associated with the release site at the synaptic ribbons. Conversely, our results suggest that Cav1.3 long isoforms, which carry ∼75% of the total IHC Ca2+ current with slow inactivation and confer high sensitivity to nifedipine and to internal EGTA, are essentially involved in recruiting SRP vesicles. Intracellular Ca2+ imaging showed that Cav1.3 long isoforms support a deep intracellular diffusion of Ca2+SIGNIFICANCE STATEMENT Auditory inner hair cells (IHCs) encode sounds into nerve impulses through fast and indefatigable Ca2+-dependent exocytosis at their ribbon synapses. We show that this synaptic process involves long and short C-terminal isoforms of the Cav1.3 Ca2+ channel that differ in the kinetics of their Ca2+-dependent inactivation and their relative sensitivity to the l-type Ca2+ channel blocker nifedipine. The short C-terminal isoforms, having fast inactivation and low sensitivity to nifedipine, mainly control the fast fusion of the readily releasable pool (RRP); that is, they encode the phasic exocytotic component. The long isoforms, with slow inactivation and great sensitivity to nifedipine, mainly regulate the vesicular replenishment of the RRP; that is, the sustained or tonic exocytosis.

Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors.

In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPA(bi)) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset. Altogether, these results identified the co-occurrence of mutations in CSF3R and CEBPA in a well-defined AML subset, which uniformly responds to JAK inhibitors and paves the way to personalized clinical trials for this disease.

GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo.

Acute myeloid leukemia (AML) is a genetically heterogeneous hematologic malignancy, which is initiated and driven by a rare fraction of leukemia stem cells (LSCs). Despite the difficulties of identifying a common LSC phenotype, there is increasing evidence that high expression of stem cell gene signatures is associated with poor clinical outcome. Identification of functionally distinct subpopulations in this disease is therefore crucial to dissecting the molecular machinery underlying LSC self-renewal. Here, we combined next-generation sequencing technology with in vivo assessment of LSC frequencies and identified the adhesion G protein-coupled receptor 56 (GPR56) as a novel and stable marker for human LSCs for the majority of AML samples. High GPR56 expression was significantly associated with high-risk genetic subgroups and poor outcome. Analysis of GPR56 in combination with CD34 expression revealed engraftment potential of GPR56(+)cells in both the CD34(-)and CD34(+)fractions, thus defining a novel LSC compartment independent of the CD34(+)CD38(-)LSC phenotype.

EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations.

The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34(+) cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events.

Exocytotic machineries of vestibular type I and cochlear ribbon synapses display similar intrinsic otoferlin-dependent Ca2+ sensitivity but a different coupling to Ca2+ channels.

The hair cell ribbon synapses of the mammalian auditory and vestibular systems differ greatly in their anatomical organization and firing properties. Notably, vestibular Type I hair cells (VHC-I) are surrounded by a single calyx-type afferent terminal that receives input from several ribbons, whereas cochlear inner hair cells (IHCs) are contacted by several individual afferent boutons, each facing a single ribbon. The specificity of the presynaptic molecular mechanisms regulating transmitter release at these different sensory ribbon synapses is not well understood. Here, we found that exocytosis during voltage activation of Ca(2+) channels displayed higher Ca(2+) sensitivity, 10 mV more negative half-maximum activation, and a smaller dynamic range in VHC-I than in IHCs. VHC-I had a larger number of Ca(2+) channels per ribbon (158 vs 110 in IHCs), but their Ca(2+) current density was twofold smaller because of a smaller open probability and unitary conductance. Using confocal and stimulated emission depletion immunofluorescence microscopy, we showed that VHC-I had fewer synaptic ribbons (7 vs 17 in IHCs) to which Cav1.3 channels are more tightly organized than in IHCs. Gradual intracellular Ca(2+) uncaging experiments revealed that exocytosis had a similar intrinsic Ca(2+) sensitivity in both VHC-I and IHCs (KD of 3.3 ± 0.6 µM and 4.0 ± 0.7 µM, respectively). In otoferlin-deficient mice, exocytosis was largely reduced in VHC-I and IHCs. We conclude that VHC-I and IHCs use a similar micromolar-sensitive otoferlin Ca(2+) sensor and that their sensory encoding specificity is essentially determined by a different functional organization of Ca(2+) channels at their synaptic ribbons.

Serum concentrations of hydroxybupropion for dose optimization of depressed patients treated with bupropion.

BACKGROUND: Bupropion is a dopamine and norepinephrine reuptake inhibitor approved for the treatment of depression and smoking cessation. According to the recently published reviews, it is a candidate for therapeutic drug monitoring (TDM) to improve therapeutic outcomes and reduce risks of intolerability or intoxication. In practice, however, the use of TDM is limited due to the chemical instability of bupropion. This investigation sought to determine if the major, active, and chemically stable metabolite 4-hydroxybupropion is a suitable measure to guide antidepressant drug therapy with bupropion. METHODS: 4-Hydroxybupropion serum levels were measured using a newly developed and validated high-performance liquid chromatography assay with ultraviolet detection. They correlated with therapeutic effects measured by the clinical global impression scale for improvement. RESULTS: The study included 52 patients (50% women). Patients who were markedly improved according to the clinical global impression scale score had significantly (P = 0.042) higher 4-hydroxybupropion serum levels than those with moderate or minimal improvement (mean ± SD, 1113 ± 576, 825 ± 398, and 475 ± 331 ng/mL, respectively). Analysis of receiver operating characteristics revealed significant predictive properties of 4-hydroxybupropion serum levels (P = 0.002) for marked improvement with a lower threshold level of 858 ng/mL. Under similar mean doses (265 ± 107 versus 239 ± 100 mg, respectively), women attained significantly higher serum levels than men (1050 ± 524 versus 589 ± 352 ng/mL, respectively) and exhibited a better therapeutic effect (P = 0.018). CONCLUSIONS: Despite multiple limitations of this naturalistic study, evidence could be given that the measurement of 4-hydroxybupropion in serum is suitable to perform TDM for bupropion. Blood levels should be above 860 ng/mL to attain therapeutic improvement. Potential sex differences in bupropion pharmacokinetics, probably due to differential activities of CYP2B6, should be taken into account when the drug is prescribed.

Serotoninergic antidepressants combination in psilocybin-assisted psychotherapy: a case report.

Psilocybin has reemerged as a promising treatment for difficult-to-treat depression (DTD). Although there is limited evidence regarding interactions between psilocybin and other psychotropic drugs, clinical trials require that patients discontinue their antidepressants before study entry to isolate the benefits of psilocybin and to minimize the risk of adverse events. We present the first case of an adult patient with DTD who received psilocybin-assisted psychotherapy (PAP) in combination with two serotoninergic antidepressants (duloxetine and vortioxetine). Since he displayed a partial response after the first PAP session, he agreed to discontinue duloxetine (but refused to stop vortioxetine) before the second PAP session to see if it could improve the therapeutic efficacy of psilocybin. However, his anxiety and depressive symptoms worsened. Psilocybin was well-tolerated in both PAP sessions; mild headaches were the main adverse effects experienced by the patient, and there were no cardiovascular safety concerns. This case report suggests that serotoninergic antidepressants combination with psilocybin appears to be safe and that antidepressant discontinuation prior to PAP may not be necessary. Since the continuation of antidepressants during PAP has the potential to improve treatment acceptability and accessibility, future research should assess whether psilocybin can be administered concurrently with antidepressants.

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment.

The potential of immune checkpoint inhibitors (ICI) may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of cancer immunotherapies is compromised by the accumulation of senescent cells in mice and in the context of therapy-induced senescence (TIS). Resistance to immunotherapy is associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells restores immune homeostasis within the tumor micro-environment (TME) and increases mice survival in response to immunotherapy. Using single-cell transcriptomic analysis, we observe that the injection of ABT263 (Navitoclax) reverses the exacerbated immunosuppressive profile of myeloid cells in the TME. Elimination of these myeloid cells also restores CD8 T cell proliferation in vitro and abrogates immunotherapy resistance in vivo. Overall, our study suggests that the use of senolytic drugs before ICI may constitute a pharmacological approach to improve the effectiveness of cancer immunotherapies.

Smarcd1 subunit of SWI/SNF chromatin-remodeling complexes collaborates with E2a to promote murine lymphoid specification.

Lymphocyte development from murine hematopoietic stem cells (HSCs) entails a loss of self-renewal capacity and a progressive restriction of developmental potential. Previous research from our laboratory suggests that specialized assemblies of ATP-dependent SWI/SNF chromatin-remodeling complexes play lineage-specific roles during murine hematopoiesis. Here, we demonstrate that the Smarcd1 subunit is essential for specification of lymphoid cell fate from multipotent progenitors. Acute deletion of Smarcd1 in murine adult hematopoiesis leads to lymphopenia, characterized by a near-complete absence of early lymphoid progenitors and mature B and T cells, while the myeloid and erythroid lineages remain unaffected. Mechanistically, we demonstrate that Smarcd1 is essential for the coordinated activation of a lymphoid gene signature in murine multipotent progenitors. This is achieved by interacting with the E2a transcription factor at proximal promoters and by regulating the activity of distal enhancers. Globally, these findings identify Smarcd1 as an essential chromatin remodeler that governs lymphoid cell fate.