Browse Articles

Non-overlapping social and sucrose reward representations in the basolateral amygdala

Animals must continually evaluate the relative value of social and nonsocial rewards to guide adaptive behavior. While both food and social stimuli engage overlapping reward networks, how these reward types are represented within specific nodes of the circuit remains unresolved. The basolateral amygdala (BLA), a region critical for valence and motivational processing, has been implicated in encoding both shared and distinct representations of social and food stimuli. Using in vivo calcium imaging in freely behaving male and female mice performing a two-choice social-sucrose operant task, we examined how individual BLA neurons encode these two different rewards within the same behavioral framework. We found that largely non-overlapping populations of BLA neurons respond to social and sucrose rewards, revealing distinct representational subspaces for each reward type. Under baseline conditions both sexes robustly encoded social and sucrose rewards, but water deprivation revealed a pronounced sex difference, shifting representations toward sucrose reward in females. Populations of sucrose reward responsive neurons in the BLA were selectively sensitive to reward omission. Specifically, sucrose-excited neurons were more strongly modulated by the absence of expected reward than sucrose-inhibited neurons, suggesting a key role for these neurons in signaling reward prediction violations. Together, these findings demonstrate that the BLA encodes social and sucrose rewards through distinct, state-dependent, and functionally heterogeneous neuronal populations, highlighting region-specific strategies for representing reward identity and internal motivational context. Significance Statement The brain’s capacity to weigh different types of rewards, like sucrose versus social interaction, is fundamental to survival yet remains poorly understood. By imaging neuronal activity in the basolateral amygdala (BLA) as mice freely choose between social and sucrose rewards, we found that largely distinct populations of BLA neurons encode each reward type. Internal state selectively altered the recruitment of reward-responsive BLA neurons in a sex-dependent manner. We further show that individual BLA neurons are differentially sensitive to the omission of expected rewards based on baseline responses. Together, these findings highlight the functional diversity through which the brain assigns value across reward modalities and dynamically adapts to changing motivational states.

Neuronal mechanisms mediating long-lasting changes in signal processing also influence neurovascular coupling in the rat hippocampus

To investigate how altered neural signal processing influences fMRI-BOLD responses in the hippocampus, we performed simultaneous in vivo electrophysiology and BOLD-fMRI in male Wistar rats during electrical stimulation of the perforant pathway. By defining input activity via applied pulses and measuring output activity through population spikes, we were able to identify qualitative and quantitative changes in signal processing once the relationship between input and output changed. An initial series of three low-intensity stimulations (LIS) induced clear, consistent BOLD responses. However, following a high-intensity stimulation (HIS) that triggered brief neuronal after-discharges, subsequent series of three identical LIS resulted in significantly attenuated BOLD responses. Electrophysiological data revealed that while total neuronal activity remained stable across all LIS, only the initial LIS induced long-lasting changes in signal processing (persisting beyond 1 minute) and transiently increased gamma band activity. By contrast, after HIS, these changes were reversed and could no longer be re-induced, coinciding with the absence of further increases in gamma band activity. Pharmacological experiments using MK801 and isoflurane further demonstrated that the mechanisms underlying long-lasting changes in signal processing also enhance LIS-induced BOLD responses. These findings suggest that positive fMRI-BOLD responses reflect functionally relevant changes in neural network properties—such as long-lasting modifications in signal processing—rather than simple increases in total neuronal output. Significance Statement An increase in BOLD fMRI signal in a specific brain region is generally interpreted as reflecting increased neuronal activity, with larger increases taken to indicate higher levels of activity. Here, we show that identical inputs can elicit stronger BOLD responses when they also induce long-lasting changes in local network properties, even when the overall activity of principal neurons remains similar. This suggests that the BOLD response is better understood as an indicator of functionally relevant changes in local network processing rather than a purely quantitative measure of neuronal activity.

NOTCHing the MSC-endothelial interplay in the HSC niche

Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals

Abstract Hematopoietic stem cells (HSCs) rely on specialized niche cells for their maintenance, yet how these regulators functionally integrate to preserve hematopoiesis remains unknown. In this study, we identified a subset of protein C receptor–positive (Procr+) endothelial cells (ECs) with progenitor-like properties in bone marrow (BM) which is critical for vascular homeostasis and regeneration after injury. Endothelial-specific ablation of Procr severely compromises BM vascular integrity and function. Beyond serving as a stem cell marker, Procr also serves as a functional signaling receptor in multicellular communication. Mechanistically, Procr binds heat shock protein A8 (HSPA8) to promote Foxc2 nuclear translocation, thereby upregulating delta-like ligand 4 (Dll4) transcription to sustain Dll4/Notch3 activation in mesenchymal stem cells (MSCs), revealing a Procr/HSPA8/Foxc2/Dll4 axis essential for EC and MSC cross talk. Through the HSPA8/Foxc2/Dll4/Notch3 axis, Procr+ ECs instruct MSC notch signaling, coordinating their adipogenic and osteogenic differentiation to maintain HSC self-renewal and myeloid output. Building on this mechanism, we demonstrated conserved functionality of Procr+ endothelial progenitor cells (EPCs) in human BM. Human PROCR+ ECs were found to similarly enhance DLL4/Notch3 signaling in MSCs, consequently preserving HSC function, confirming their therapeutic relevance. Our work highlights that Procr+ EPCs sustain vascular integrity and govern MSC-dependent HSC maintenance, offering targeted clinical strategies for niche regeneration.

Li C, Wu B, Li Y, et al. Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness. <i>Blood</i> . 2022;140(15):1686-1701.

Haploidentical transplant, gene therapy, and standard care in sickle cell disease: a cost-effectiveness analysis

Abstract Nonmyeloablative-related haploidentical allogeneic stem cell transplantation (NMAC-HID allo-HSCT) has emerged as an additional treatment to achieve durable remission in sickle cell disease (SCD), a prevalent blood disorder characterized by painful vaso-occlusive crises and chronic anemia. The standard of care (SOC) for SCD includes hydroxyurea, pain management, and blood transfusion, but patients with SCD still lose several decades of life expectancy. Gene therapy (GT) for SCD is the other treatment for lifelong disease amelioration in SCD, with accessibility limited by cost and manufacturing capacity in the United States and globally. Two recent prospective studies that evaluated NMAC-HID allo-HSCT validated haploidentical allotransplantation as an efficacious and accessible treatment option in the era of GT. Given the ongoing price negotiation across jurisdictions for GT implementation and the absence of cost-effectiveness data comparing NMAC-HID allo-HSCT and GT, we conducted a cost-effectiveness analysis of NMAC-HID allo-HSCT vs GT vs SOC for adults and children living with SCD. The primary outcomes were the incremental cost-effectiveness ratio and the net monetary benefits across these 3 strategies. The secondary outcome was the maximum cost-effective threshold price for GT compared with NMAC-HID allo-HSCT. Treatment with SOC, NMAC-HID allo-HSCT, and GT accrued 14.3, 20.1, and 22.1 quality-adjusted life-years at costs of $1.22 million, $1.15 million, and $2.75 million, respectively. NMAC-HID allo-HSCT was the cost-effective strategy compared with GT in 100% of 10 000 Monte Carlo iterations across the base case and all scenario analyses. The maximum cost-effective thresholds for GT vs SOC were $1.4 million in the United States and $4200 to $22 000 across India, Nigeria, and Tanzania, depending on willingness-to-pay thresholds.

Granulopoiesis under attack by mutant IDH1

Abro B, Maurer MJ, Habermann TM, et al. Real-world impact of differences in the WHO and ICC classifications of non-Hodgkin lymphoma: a LEO cohort study analysis. <i>Blood</i> . 2024;144(19):2063-2066.

<i>IDH2</i> clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma

Abstract Lenalidomide, a maintenance treatment in multiple myeloma first-line therapy, increases the risk of secondary malignancies, including B-cell precursor acute lymphoblastic leukemia (B-ALL). We present a comprehensive molecular characterization of 57 patients with lenalidomide-associated B-ALL (LenB-ALL), revealing 3 mutational subgroups: (1) TP53mt (30%); (2) IDH2mt (p.R140Q) (23%); and (3) other, including NRAS/KRASmt. Remarkably, IDH2 R140Q mutations were highly enriched in LenB-ALL compared with those in primary B-ALL (P&amp;lt; .001). Furthermore, IKZF1 intragenic deletions, often subclonal and likely RAG recombinase-mediated, were observed in 54% (7/13) of IDH2mt patients with LenB-ALL. IDH2 mutations were not restricted to the leukemic clone: they persisted during measurable residual disease–negative remission and were identified in lymphoid as well as myeloid cell populations using fluorescence-activated cell sorting and single-cell RNA sequencing. This indicates a preleukemic origin of the IDH2 mutation within the context of clonal hematopoiesis. Transcriptomic and DNA methylation analyses revealed a distinct gene expression profile and a DNA hypermethylation phenotype in IDH2mt LenB-ALL, including IDH2mt-specific as well as lenalidomide-associated features. We propose that lenalidomide promotes the expansion of IDH2-mutated clonal hematopoiesis and, via IKAROS downregulation, induces a maturation arrest at the B-cell precursor stage. Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. All these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.

Mutant IDH1 blocks neutropoiesis by repressing myeloid progenitor programs

Abstract IDH1 and IDH2 are frequently mutated in various cancers, including acute leukemias. However, the distinct mechanisms by which mutant IDH1 or IDH2 drive hematopoietic neoplasms remain poorly understood. Here, we analyzed DNA methylation in IDH1- and IDH2-mutant acute myeloid leukemia and found neutrophil lineage-specific epigenetic alterations in IDH1-mutant patients that went along with severely impaired neutrophil differentiation. Transcriptional analysis of normal hematopoiesis in humans and mice revealed a strong physiological upregulation of IDH1/Idh1 in myeloid progenitors. To study the functional effects of Idh1 mutations on hematopoiesis in a preleukemic setting, we used a genetically engineered inducible mouse model expressing a heterozygous Idh1 mutation under control of the endogenous promotor. Our study revealed a cell-intrinsic block in neutrophil differentiation caused by repression of myeloid transcription programs in neutrophil progenitors. This included impaired expression of Cebpe, which encodes a key transcription factor regulating neutrophil differentiation. Reactivation of Cebpe expression, by overexpression of its upstream regulator Cebpa or following treatment with hypomethylating agents, restored differentiation, indicating that the differentiation block is reversible. In summary, we found a reversible, preleukemic impairment of neutrophil differentiation in IDH1-mutant hematopoiesis that correlates with elevated IDH1 expression in myeloid progenitors and likely explains the strong association of IDH1 mutations with myeloid neoplasms.

IKAROS descent and rise of lenalidomide-associated B-ALL

Dissecting polycomb complexes for enhanced fetal hemoglobin production

Abstract Polycomb repressive complex 1 (PRC1) and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin (Hb) production, a process whose reversal is a goal for the treatment of sickle cell disease and β-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal Hb (HbF) can be reactivated in adult erythroid cells by selective perturbations of PRC1 or PRC2 components without complete loss of PRC function. A high-density CRISPR–CRISPR-associated protein 9 (Cas9) mutagenesis screen identified a region in EZH2 in which Cas9 induced exon 14 skipping (EZH2Δ14). EZH2Δ14, which lacks a portion of the CXC domain, relieves HbF repression while largely maintaining cellular fitness. EZH2Δ14 retains H3K27 methylation and repression of a PRC target gene subset. Experiments in cells derived from mice bearing human β-globin genes confirm that pathways mediating EZH2 control of HbF expression can function in a mouse model of HBG switching. These findings demonstrate that partial disruption of PRC can yield selective phenotypes, highlighting the therapeutic potential of targeting nonenzymatic domains within chromatin-modifying complexes.

Precision targeting of fetal hemoglobin repressors

How I utilize somatic alterations in the diagnosis, risk stratification, and therapy of hypocellular bone marrow failure

Abstract Hypocellular bone marrow failure (BMF) may be acquired due to immune-mediated disease, the prototype being immune aplastic anemia (IAA), or inherited, due to germ line defects in genes important for hematopoietic stem cell function and maintenance (inherited BMF syndromes [IBMFS]). Proper diagnosis of the underlying etiology of hypocellular BMF, particularly distinguishing IAA, myelodysplastic syndrome (MDS; most relevant in this setting is hypoplastic MDS), and the IBMFS, is important given the differences in clinical management. Clonal hematopoiesis (CH), in this context comprising somatic mutations or chromosomal abnormalities, is incorporated into standard algorithms for classification, risk stratification, and treatment decisions for hematologic malignancies, but the clinical significance in BMF is not well established. Disease-specific clonal signatures have been reported across the BMF spectrum, and here, we present how distinct patterns of CH can aid in distinguishing different etiologies of hypocellular BMF. In addition, detection of somatic alterations in many BMF disorders can estimate risk for secondary myeloid neoplasms, guide surveillance and, in some instances, allow for early therapeutic intervention.

Pound wise, penny foolish: improving value in SCD care

Anti-BCMA/GPRC5D CAR T cells in patients with relapsed or refractory multiple myeloma who have extraosseous extramedullary disease

Abstract Patients with relapsed or refractory multiple myeloma (RRMM) with extraosseous extramedullary disease (EMD) have inferior outcomes and lack effective therapies. We developed anti–B-cell maturation antigen (anti-BCMA)/G protein–coupled receptor, class C group 5 member D (GPRC5D) bispecific chimeric antigen receptors (CARs) to investigate the activity and safety of the CAR T cells in patients with extraosseous EMD. In this single-arm, open-label, phase 2 trial, we enrolled 37 patients with RRMM with extraosseous EMD, and anti-BCMA/GPRC5D bispecific CAR T cells were administered at 2.0 × 106 CAR T cells per kg. At a median follow-up of 10.1 months (interquartile range, 6.4-19.1), 36 of 37 patients (97%) obtained an overall response and measurable residual disease negativity, including 16 (43%) with stringent complete response. The median progression-free survival was 5.8 months (95% confidence interval, 2.2-9.4), and the median overall survival was not reached. The most common grade 3 or worse adverse events were hematologic toxicities (except lymphopenia; 37/37). Twenty-seven patients (73%) experienced cytokine release syndrome, all cases of which were grade 1 or 2. Two patients (5%) had grade 1 or 3 immune effector cell–associated neurotoxicity syndrome. These findings support that anti-BCMA/GPRC5D bispecific CAR T cells induced a high response rate in patients with RRMM with extraosseous EMD, and the safety profile was manageable. This ongoing trial is registered at www.clinicaltrials.gov as NCT05509530.

Bispecific CAR T for extramedullary myeloma: a minute waltz

Biosimilars approved for hematology use: lessons from comparative efficacy studies and comparative analytical assessments

Abstract Biosimilars used in hematology have been at the forefront of biosimilar development since the first US approval in 2015 of a filgrastim product, with &amp;gt;80 now licensed by the US Food and Drug Administration (FDA). Developers traditionally submitted data from a comparative analytical assessment (CAA) and clinical studies, often including a comparative efficacy study (CES), to support demonstrating their product is “highly similar” to and has “no clinically meaningful differences” from its reference product (RP). However, growing scientific confidence in the analytical comparisons between biosimilars and their RP included in the CAA has prompted the FDA and global regulators to reconsider the utility of CESs. Recently, the FDA published updated recommendations on the need for a CES in biosimilar programs. As approvals for hematologic biosimilars span the entire history of FDA biosimilar development across a breadth of patient ages and diseases, reexamining these programs provides valuable insights into the evolving role of the CES in the past and its role in the future. In this review, we present a historical overview of the development programs for all FDA-approved hematologic biosimilars in the context of an emerging global consensus recognizing that the CAA is more sensitive than the CES for predicting biosimilarity.

ELN-DAVID recommendations for NGS-based <i>FLT3</i> -ITD MRD testing for patients with acute myeloid leukemia

Abstract FLT3-internal tandem duplication measurable residual disease testing for patients in remission from acute myeloid leukemia is now recommended by the recently updated clinical standard-of-care guidelines. This companion technical note provides important laboratory and clinical recommendations regarding such testing.

A Pyridine Mediator Enables High‐Efficiency, Long‐Cycling Anode‐Less/Free Lithium–Sulfur Batteries With Li ₂ S Cathodes

ABSTRACT Lithium sulfide (Li 2 S) is a promising high‐capacity cathode material. Importantly, it can provide lithium source, enabling lithium batteries with an anode‐less/free configuration. However, Li 2 S suffers from poor conductivity, high polarization, low material utilization, as well as the shuttle effect, severely restricting the long cycling performance of batteries. Herein, lithium pyridine‐2‐thiolate (PySLi) is proposed as a multifunctional mediator for Li 2 S‐based anode‐less/free batteries. It is revealed that PySLi can modify the reaction pathway of Li 2 S, comprehensively enhancing its electrochemical redox kinetics and stability. Results show that the energy efficiency of the Li||Li 2 S cell with PySLi stabilizes at ∼80% in the full‐scale range from 0.1 C to 3 C rate, which is much higher than that without PySLi (49% at 0.1 C and 22% at 3 C). The stability of the lithium metal anode is also improved, maintaining a high coulombic efficiency of &gt;98% for 200 cycles and stable lithium stripping/plating behavior for 1000 h. Moreover, an anode‐free battery based on Li 2 S cathode works normally for 150 cycles, and an anode‐less pouch cell retains steady performance for 200 cycles. This multifunctional mediator provides a new strategy for the application of Li 2 S and stable anode‐less/free batteries with high energy density.