Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a clonal hematopoietic stem cell (HSC) disorder, PV is a neoplasm but its driver mutations result in overproduction of morphologically and functionally normal blood cells. PV arises in an HSC but it can present initially as isolated erythrocytosis, leukocytosis, thrombocytosis, or any combination of these together with splenomegaly or myelofibrosis, and it can take years for a true panmyelopathy to appear. PV shares the same JAK2 mutation as essential thrombocytosis and primary myelofibrosis, but erythrocytosis only occurs in PV. However, unlike secondary causes of erythrocytosis, in PV, the plasma volume is frequently expanded, masking the erythrocytosis and making diagnosis difficult if this essential fact is ignored. PV is not a monolithic disorder: female patients deregulate fewer genes and clinically behave differently than their male counterparts, while some PV patients are genetically predisposed to an aggressive clinical course. Nevertheless, based on what we have learned over the past century, most PV patients can lead long and productive lives. In this review, using clinical examples, I describe how I diagnose and manage PV in an evidence-based manner without relying on chemotherapy.

Arsenic trioxide and all-trans retinoic acid have become the frontline treatments for patients with acute promyelocytic leukemia (APL). Despite the long wait for an oral arsenic drug, a commercially available agent, realgar-indigo naturalis formula (RIF), was not launched in China until 2009. Since then, over 5000 APL patients have been treated with oral RIF in China. Oral arsenic not only shows a clinical efficacy comparable to that of IV formulations but also displays a better safety profile, improved quality of life, and lower medical costs for patients. The promising results promote incorporating an outpatient postremission therapy model into clinical practice for both low-risk and high-risk APL patients in China. In this review, we discuss the evolution of oral arsenic RIF in the treatment of APL, with a special focus on how to address the related complications during induction therapy.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that consistently precedes multiple myeloma (MM) with a 1% risk of progression per year. Recent advances have improved understanding of the complex genetic and immunologic factors that permit progression from the aberrant plasma cell clone to MGUS and overt MM. Additional evidence supports bidirectional interaction of MGUS cells with surrounding cells in the bone marrow niche that regulates malignant transformation. However, there are no robust prognostic biomarkers. Herein we review the current body of literature on the biology of MGUS and provide a rationale for the improved identification of high-risk MGUS patients who may be appropriate for novel clinical interventions to prevent progression or eradicate premalignant clones prior to the development of overt MM.

Cancer is the leading cause of death for HIV-infected persons in economically developed countries, even in the era of antiretroviral therapy (ART). Lymphomas remain a leading cause of cancer morbidity and mortality for HIV-infected patients and have increased incidence even in patients optimally treated with ART. Even limited interruptions of ART can lead to CD4 cell nadirs and HIV viremia, and increase the risk of lymphoma. The treatment of lymphoma is now similar for HIV-infected patients and the general population: patients with good HIV control can withstand intensive therapies appropriate to the lymphoma, including autologous and even allogeneic hematopoietic stem cell transplantation. Nonetheless, HIV-related lymphomas have unique aspects, including differences in lymphoma pathogenesis, driven by the presence of HIV, in addition to coinfection with oncogenic viruses. These differences might be exploited in the future to inform therapies. The relative incidences of lymphoma subtypes also differ in the HIV-infected population, and the propensity to advanced stage, aggressive presentation, and extranodal disease is higher. Other unique aspects include the need to avoid potential interactions between ART and chemotherapeutic agents, and the need for HIV-specific supportive care, such as infection prophylaxis. Despite these specific challenges for cancer treatment in the setting of HIV infection, the care of these patients has progressed sufficiently that recent guidelines from the American Society of Clinical Oncology advocate the inclusion of HIV-infected patients alongside HIV- patients in cancer clinical trials when appropriate.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

RNA-binding proteins (RBPs) regulate fundamental processes, such as differentiation and self-renewal, by enabling the dynamic control of protein abundance or isoforms or through the regulation of noncoding RNA. RBPs are increasingly appreciated as being essential for normal hematopoiesis, and they are understood to play fundamental roles in hematological malignancies by acting as oncogenes or tumor suppressors. Alternative splicing has been shown to play roles in the development of specific hematopoietic lineages, and sequence-specific mutations in RBPs lead to dysregulated splicing in myeloid and lymphoid leukemias. RBPs that regulate translation contribute to the development and function of hematological lineages, act as nodes for the action of multiple signaling pathways, and contribute to hematological malignancies. These insights broaden our mechanistic understanding of the molecular regulation of hematopoiesis and offer opportunities to develop disease biomarkers and new therapeutic modalities.

Mantle cell lymphoma (MCL) is a unique type of non-Hodgkin lymphoma characterized by the overexpression of cyclin D1. MCL patients typically live for years but experience multiple relapses. Acalabrutinib is a novel second-generation oral Bruton tyrosine kinase inhibitor approved by the US Food and Drug Administration for relapsed MCL based on a clinical trial demonstrating an overall response rate of 81%. It provides a valuable new treatment option for MCL patients and is now being tested upfront.

Anticoagulant therapy is the most effective strategy to prevent arterial and venous thromboembolism, but treating older individuals is challenging, because increasing age, comorbidities, and polypharmacy increase the risk of both thrombosis and bleeding. Warfarin and non-vitamin K antagonist oral anticoagulants are underused and often underdosed in the prevention of stroke in older patients with atrial fibrillation because of concerns about the risk of bleeding. Poor adherence to anticoagulant therapy is also an issue for older patients with atrial fibrillation and those at risk of recurrent pulmonary embolism. In this review, we present 5 clinical cases to illustrate common challenges with anticoagulant use in older patients and discuss our approach to institute safe and effective antithrombotic therapy.

Evidence-based recommendations have been established for treatment of chronic myeloid leukemia (CML) in adults treated with tyrosine kinase inhibitors (TKIs), but the rarity of this leukemia in children and adolescents makes it challenging to develop similar recommendations in pediatrics. In addition to imatinib, which was approved for pediatric CML in 2003, the second-generation TKIs dasatinib and nilotinib were recently approved for use in children, expanding the therapeutic options and pushing allogeneic stem cell transplantation to a third-line treatment of most pediatric cases. Yet, without sufficient data on efficacy and safety specific to pediatric patients, the selection of a TKI continues to rely on clinical experience in adults. Here, we present 4 case scenarios highlighting common yet challenging issues encountered in the treatment of pediatric CML (suboptimal response, poor treatment adherence, growth retardation, and presentation in advanced phases). Limited experience with very young children, the transition of teenagers to adult medicine, and the goal of achieving treatment-free remission for this rare leukemia are additional significant obstacles that require further clinical investigation through international collaboration.

Mutations in the cytosolic 5' nucleotidase II (NT5C2) gene drive resistance to thiopurine chemotherapy in relapsed acute lymphoblastic leukemia (ALL). Mechanistically, NT5C2 mutant proteins have increased nucleotidase activity as a result of altered activating and autoregulatory switch-off mechanisms. Leukemias with NT5C2 mutations are chemoresistant to 6-mercaptopurine yet show impaired proliferation and self-renewal. Direct targeting of NT5C2 or inhibition of compensatory pathways active in NT5C2 mutant cells may antagonize the emergence of NT5C2 mutant clones driving resistance and relapse in ALL.

Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired leukocyte recruitment, ingestion, and/or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function in which a combination of host defense and inflammatory complications are prominent, including nicotinamide dinucleotide phosphate oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency.

Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood-endothelial cell (EC) barrier and exerting effector cell functions. The neutrophil recruitment cascade to inflamed tissues involves elements of neutrophil rolling, firm adhesion, and crawling onto the EC surface before extravasating by breaching the EC barrier. The interaction between neutrophils and ECs occurs via various adhesive modules and is a critical event determining the mode of neutrophil transmigration, either at the EC junction (paracellular) or directly through the EC body (transcellular). Once thought to be a homogenous entity, new evidence clearly points to the plasticity of neutrophil functions. This review will focus on recent advances in our understanding of the mechanism of the neutrophil transmigration process. It will discuss how neutrophil-EC interactions and the subsequent mode of diapedesis, junctional or nonjunctional, can be context dependent and how this plasticity may be exploited clinically.

Neutrophils are an absolutely essential part of the innate immune system, playing an essential role in the control of infectious diseases but more recently are also being viewed as important players in tissue repair. Neutrophils are able to counteract an infection through phagocytosis and/or the release of neutrophil extracellular traps (NETs). By contrast, neutrophils help repair damaged tissues, limiting NET production but still phagocytosing debris. However, when inflammation is recurrent, or the inciting agent persists, neutrophils through a frustrated inability to resolve the problem can release NETs to exacerbate tissue damage during inappropriate inflammation. In this review, we discuss the mechanisms of NET formation, as well as the apparent paradoxical role of neutrophils and NETs in host defense, chronic inflammation, and tissue disrepair.

The microbiota has emerged as an important regulator of the host immunity by the induction, functional modulation, or suppression of local and systemic immune responses. In return, the host immune system restricts translocation and fine tunes the composition and distribution of the microbiota to maintain a beneficial symbiosis. This paradigm applies to neutrophils, a critical component of the innate immunity, allowing their production and function to be influenced by microbial components and metabolites derived from the microbiota, and engaging them in the process of microbiota containment and regulation. The cross talk between neutrophils and the microbiota adjusts the magnitude of neutrophil-mediated inflammation on challenge while preventing neutrophil responses against commensals under steady state. Here, we review the major molecular and cellular mediators of the interactions between neutrophils and the microbiota and discuss their interplay and contribution in chronic inflammatory diseases and cancer.

The niche that supports hematopoietic stem and progenitor cells (HSPCs) in the bone marrow is a highly dynamic structure. It maintains core properties of HSPCs in the steady state, and modulates their proliferation and differentiation in response to changing physiological demands or pathological insults. The dynamic and environment-sensing properties of the niche are shared by the innate immune system. Thus, it is not surprising that innate immune cells, including macrophages and neutrophils, are now recognized as important regulators of the hematopoietic niche and, ultimately, of the stem cells from which they derive. This review synthesizes emerging concepts on niche regulation by immune cells, with a particular emphasis on neutrophils. We argue that the unique developmental, circadian, and migratory properties of neutrophils underlie their critical contributions as regulators of the hematopoietic niche.

Reactive and clonal neutrophil expansion has been associated with thrombosis, suggesting that neutrophils play a role in this process. However, although there is no doubt that activated monocytes trigger coagulation in a tissue factor-dependent manner, it remains uncertain whether stimulated neutrophils can also directly activate coagulation. After more than a decade of debate, it is now largely accepted that normal human neutrophils do not synthetize tissue factor, the initiator of the extrinsic pathway of coagulation. However, neutrophils may passively acquire tissue factor from monocytes. Recently, the contact system, which initiates coagulation via the intrinsic pathway, has been implicated in the pathogenesis of thrombosis. After the recent description of neutrophil extracellular trap (NET) release by activated neutrophils, some animal models of thrombosis have demonstrated that coagulation may be enhanced by direct NET-dependent activation of the contact system. However, there is currently no consensus on how to assess or quantify NETosis in vivo, and other experimental animal models have failed to demonstrate a role for neutrophils in thrombogenesis. Nevertheless, it is likely that NETs can serve to localize other circulating coagulation components and can also promote vessel occlusion independent of fibrin formation. This article provides a critical appraisal of the possible roles of neutrophils in thrombosis and highlights some existing knowledge gaps regarding the procoagulant activities of neutrophil-derived extracellular chromatin and its molecular components. A better understanding of these mechanisms could guide future approaches to prevent and/or treat thrombosis.

Neutrophils act as the body's first line of defense against infection and respond to diverse inflammatory cues, including cancer. Neutrophils display plasticity, with the ability to adapt their function in different inflammatory contexts. In the tumor microenvironment, neutrophils have varied functions and have been classified using different terms, including N1/N2 neutrophils, tumor-associated neutrophils, and polymorphonuclear neutrophil myeloid-derived suppressor cells (PMN-MDSCs). These populations of neutrophils are primarily defined by their functional phenotype, because few specific cell surface markers have been identified. In this review, we will discuss neutrophil polarization and plasticity and the function of proinflammatory/anti-inflammatory and protumor/antitumor neutrophils in the tumor microenvironment. We will also discuss how neutrophils with the ability to suppress T-cell activation, referred to by some as PMN-MDSCs, fit into this paradigm.

The molecular causes of many inherited platelet disorders are being unraveled. Next-generation sequencing facilitates diagnosis in 30% to 50% of patients. However, interpretation of genetic variants is challenging and requires careful evaluation in the context of a patient's phenotype. Before detailed testing is initiated, the treating physician and patient should establish an understanding of why testing is being performed and discuss potential consequences, especially before testing for variants in genes associated with an increased risk for hematologic malignancies.

Liquid biopsies have been considered the holy grail in achieving effective cancer management, with blood tests offering a minimally invasive, safe, and sensitive alternative or complementary approach for tissue biopsies. Currently, blood-based liquid biopsy measurements focus on the evaluation of biomarker types, including circulating tumor DNA, circulating tumor cells, extracellular vesicles (exosomes and oncosomes), and tumor-educated platelets (TEPs). Despite the potential of individual techniques, each has its own advantages and disadvantages. Here, we provide further insight into TEPs.

Genomics is affecting all areas of medicine. In transfusion medicine, DNA-based genotyping is being used as an alternative to serological antibody-based methods to determine blood groups for matching donor to recipient. Most antigenic polymorphisms are due to single nucleotide polymorphism changes in the respective genes, and DNA arrays that target these changes have been validated by comparison with antibody-based typing. Importantly, the ability to test for antigens for which there are no serologic reagents is a major medical advance to identify antibodies and find compatible donor units, and can be life-saving. This review summarizes the evolving use and applications of genotyping for red cell and platelet blood group antigens affecting several areas of medicine. These include prenatal medicine for evaluating risk of fetal or neonatal disease and candidates for Rh-immune globulin; transplantation for bone marrow donor selection and transfusion support for highly alloimmunized patients and for confirmation of A2 status of kidney donors; hematology for comprehensive typing for patients with anemia requiring chronic transfusion; and oncology for patients receiving monoclonal antibody therapies that interfere with pretransfusion testing. A genomics approach allows, for the first time, the ability to routinely select donor units antigen matched to recipients for more than ABO/RhD to reduce complications. Of relevance, the growth of whole-genome sequencing in chronic disease and for general health will provide patients' comprehensive extended blood group profile as part of their medical record to be used to inform selection of the optimal transfusion therapy.