Background Acute myeloid leukemia (AML) is associated with a dismal prognosis. Immune checkpoint blockade (ICB) to induce antitumor activity in AML patients has yielded mixed results. Despite the pivotal role of B cells in antitumor immunity, a comprehensive assessment of B lymphocytes within AML’s immunological microenvironment along with their interaction with ICB remains rather constrained. Methods We performed an extensive analysis that involved paired single-cell RNA and B-cell receptor (BCR) sequencing on 52 bone marrow aspirate samples. These samples included 6 from healthy bone marrow donors (normal), 24 from newly diagnosed AML patients (NewlyDx), and 22 from 8 relapsed or refractory AML patients (RelRef), who underwent assessment both before and after azacitidine/nivolumab treatment. Results We delineated nine distinct subtypes of B cell lineage in the bone marrow. AML patients exhibited reduced nascent B cell subgroups but increased differentiated B cells compared with healthy controls. The limited diversity of BCR profiles and extensive somatic hypermutation indicated antigen-driven affinity maturation within the tumor microenvironment of RelRef patients. We established a strong connection between the activation or stress status of naïve and memory B cells, as indicated by AP-1 activity, and their differentiation state. Remarkably, atypical memory B cells functioned as specialized antigen-presenting cells closely interacting with AML malignant cells, correlating with AML stemness and worse clinical outcomes. In the AML microenvironment, plasma cells demonstrated advanced differentiation and heightened activity. Notably, the clinical response to ICB was associated with B cell clonal expansion and plasma cell function. Conclusions Our findings establish a comprehensive framework for profiling the phenotypic diversity of the B cell lineage in AML patients, while also assessing the implications of immunotherapy. This will serve as a valuable guide for future inquiries into AML treatment strategies.

Background and Clinical Significance: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system. Case Presentation: We present the case of an eight-month-old infant with influenza A(H1N1) who presented with seizures, hepatosplenomegaly, cytopenias, and markedly elevated levels of ferritin, IL-18, and CXCL9, raising concern for HLH. Despite initiation of HLH-directed and antiviral therapy, she succumbed to cardiorespiratory failure. Genetic testing revealed heterozygous variants in LYST and NLRC4, suggesting a potential genetic predisposition. Conclusions: This case underscores the challenge of distinguishing primary from secondary HLH and highlights the importance of balancing aggressive immunosuppression with infection control. Early genetic and cytokine profiling may assist in guiding personalized treatment strategies, enabling targeted interventions that avoid excessive immunosuppressive treatment in cases of reactive hyperinflammation while facilitating timely escalation of therapy in true or refractory HLH.