Genetic and epigenetic factors interacting with clonal hematopoiesis resulting in chronic myelomonocytic leukemia Purpose of review Since 2016, the WHO has recognized the significant phenotypic heterogeneity of chronic myelomonocytic leukemia (CMML) as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap disease. Although sharing many somatic mutations with MDS and MPN, the purpose of this review is to put recent biological findings of CMML in the context of evolutionary theory, highlighting it as a distinct evolutionary trajectory occurring in the context of clonal hematopoiesis. Recent findings Clonal hematopoiesis of indeterminate potential (CHIP), with a mutational spectrum and prevalence correlated with age, has been defined. Enriched in DNMT3A, TET2, and ASXL1 mutations, clonal evolution can progress into various evolutionary trajectories including CMML. Impact of founder mutations (primarily TET2) on increased hematopoietic stem cell fitness has been well characterized. Epistatic interactions between mutations and epigenetic events have been explored, both in CMML and its pediatric counterpart juvenile myelomonocytic leukemia, including CMML transformation to acute myeloid leukemia. Together, these findings have contributed significantly toward CMML evolutionary dynamics. Summary Despite relatively few ‘driver’ mutations in CMML, evolutionary development of chronic leukemia remains incompletely understood. Recent studies have shed light on the importance of studying epigenetic consequences of mutations and epistasis between key mutations to better understand clonal architecture and evolutionary dynamics.

Family studies of warts, hypogammaglobulinemia, immunodeficiency, myelokathexis syndrome Purpose of review WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. We reviewed clinical manifestations in 24 patients in 9 families to expand understanding of this syndrome. Recent findings Warts, cellulitis and respiratory infections are common in patients with WHIMs. Less commonly these patients have congenital heart disease, human papilloma virus-associated malignancies (cervical and vulvular) and lymphomas. Hearing loss because of recurrent otitis media is another important complication. Treatment with granulocyte colony-stimulating factor is controversial; this review indicates that it is effective to prevent and treat infections based upon long-term observations of patients enrolled in the Severe Chronic Neutropenia International Registry. Understanding the natural history and diversity of this syndrome are important for ongoing clinical trials of novel agents to treat WHIMs. Summary WHIM syndrome has diverse manifestations; some features occur consistently in almost all patients, for example, neutropenia, lymphocytopenia and mild hypogammaglobulinemia. However, the clinical consequences are quite variable across patient cohorts and within families. Each complication is important as a cause for morbidity and a source for patient and family concerns.

Registries for study of nonmalignant hematological diseases: the example of the Severe Chronic Neutropenia International Registry Purpose of review Registries provide ‘real world’ perspectives on the natural history and outcomes for many clinical conditions. The purpose of this review is to identify registries for nonmalignant hematological disease and to describe the operation of a successful long-term registry for patients with severe chronic neutropenia. Recent findings There was an upswing in registries about 20 years ago, based on optimism about their utility to improve patient care. To show value, registries must define outcomes for populations of patients with specific medical conditions and the effects of treatment. This is challenging for many reasons. The Severe Chronic Neutropenia International Registry is an example of a successful registry. This report describes underlying reasons for its success. Summary Registries are important to organize and analyze clinical information across geographic, ethnic and social boundaries. They are also challenging to organize, administer and support.

Transcription factor and cytokine regulation of eosinophil lineage commitment Purpose of review Lineage commitment is governed by instructive and stochastic signals, which drive both active induction of the lineage program and repression of alternative fates. Eosinophil lineage commitment is driven by the ordered interaction of transcription factors, supported by cytokine signals. This review summarizes key findings in the study of eosinophil lineage commitment and examines new data investigating the factors that regulate this process. Recent findings Recent and past studies highlight how intrinsic and extrinsic signals modulate transcription factor network and lineage decisions. Early action of the transcription factors C/EBPα and GATA binding protein-1 along with C/EBPε supports lineage commitment and eosinophil differentiation. This process is regulated and enforced by the pseudokinase Trib1, a regulator of C/EBPα levels. The cytokines interleukin (IL)-5 and IL-33 also support early eosinophil development. However, current studies suggest that these cytokines are not specifically required for lineage commitment. Summary Together, recent evidence suggests a model where early transcription factor activity drives expression of key eosinophil genes and cytokine receptors to prime lineage commitment. Understanding the factors and signals that control eosinophil lineage commitment may guide therapeutic development for eosinophil-mediated diseases and provide examples for fate choices in other lineages.

Platelets as key players in inflammation and infection Purpose of review This review highlights recent insights into the role of platelets in acute inflammation and infection. Recent findings Platelets exhibit intravascular crawling behavior and can collect and bundle bacteria. In addition, platelets are key in promoting intravascular thrombus formation in infection, a process termed ‘immunothrombosis’, which contributes to pathogen containment, but also potentially damages the host. Platelets are at the nexus of leukocyte recruitment and activation, yet they are at the same time crucial in preventing inflammation-associated hemorrhage and tissue damage. This multitasking requires specific receptors and pathways, depending on stimulus, organ and effector function. Summary New findings highlight the complex interplay of innate immunity, coagulation and platelets in inflammation and infection, and unravel novel molecular pathways and effector functions. These offer new potential therapeutic approaches, but require further extensive research to distinguish treatable proinflammatory from host–protective pathways.

Myeloid cell and cytokine interactions with chimeric antigen receptor-T-cell therapy: implication for future therapies Purpose of review Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary tool in the treatment of cancer. CAR-T cells exhibit their effector functions through the recognition of their specific antigens on tumor cells and recruitment of other immune cells. However, this therapy is limited by the development of severe toxicities and modest antitumor activity in solid tumors. The host and tumor microenvironment interactions with CAR-T cells play an important role in orchestrating CAR-T-cell functions. Specifically, myeloid lineage cells and their cytokines critically influence the behavior of CAR-T cells. Here, we review the specific effects of myeloid cell interactions with CAR-T cells, their impact on CAR-T-cell response and toxicities, and potential efforts to modulate myeloid cell effects to enhance CAR-T-cell therapy efficacy and reduce toxicities. Recent findings Independent studies and correlative science from clinical trials indicate that inhibitory myeloid cells and cytokines contribute to the development of CAR-T-cell-associated toxicities and impairment of their effector functions. Summary These findings illuminate a novel way to reduce CAR-T-cell-associated toxicities and enhance their efficacy through the modulation of myeloid lineage cells and inhibitory cytokines.