The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology.

Only 30% of patients who require an allogeneic hematopoietic cell transplant will have an HLA-matched sibling donor. A search for an unrelated donor will be undertaken for patients without a matched family donor. However, many patients, particularly patients of diverse racial and ethnic backgrounds, may not be able to rapidly identify a suitably matched unrelated donor. Three alternative graft sources, umbilical cord blood (UCB), haploidentical (haplo)-related donor, and mismatched unrelated donor (MMUD) are available. UCB is associated with decreased GVHD, but hematologic recovery and immune reconstitution are slow. Haplo-HCT is characterized by donor availability for transplantation and after transplantation adoptive cellular immunotherapy but may be complicated by a high risk of graft failure and relapse. A MMUD transplant may also be an option, but GVHD may be of greater concern. Phase 2 studies have documented advances in HLA typing, GVHD prophylaxis, and infection prevention, which have improved survival. The same patient evaluated in different transplant centers may be offered MMUD, UCB, or haplo-HCT depending on center preference. In this review, we discuss the rationale for donor choice and the need of phase 3 studies to help answer this important question.

Macrophage-colony stimulating factor (CSF-1) signaling through its receptor (CSF-1R) promotes the differentiation of myeloid progenitors into heterogeneous populations of monocytes, macrophages, dendritic cells, and bone-resorbing osteoclasts. In the periphery, CSF-1 regulates the migration, proliferation, function, and survival of macrophages, which function at multiple levels within the innate and adaptive immune systems. Macrophage populations elicited by CSF-1 are associated with, and exacerbate, a broad spectrum of pathologies, including cancer, inflammation, and bone disease. Conversely, macrophages can also contribute to immunosuppression, disease resolution, and tissue repair. Recombinant CSF-1, antibodies against the ligand and the receptor, and specific inhibitors of CSF-1R kinase activity have been each been tested in a range of animal models and in some cases, in patients. This review examines the potential clinical uses of modulators of the CSF-1/CSF-1R system. We conclude that CSF-1 promotes a resident-type macrophage phenotype. As a treatment, CSF-1 has therapeutic potential in tissue repair. Conversely, inhibition of CSF-1R is unlikely to be effective in inflammatory disease but may have utility in cancer.

Although platelets are the smallest cells in the blood, they are implied in various processes ranging from immunology and oncology to thrombosis and hemostasis. Many large-scale screening programs, genome-wide association, and "omics" studies have generated lists of genes and loci that are probably involved in the formation or physiology of platelets under normal and pathologic conditions. This creates an increasing demand for new and improved model systems that allow functional assessment of the corresponding gene products in vivo. Such animal models not only render invaluable insight in the platelet biology, but in addition, provide improved test systems for the validation of newly developed anti-thrombotics. This review summarizes the most important models to generate transgenic platelets and to study their influence on platelet physiology in vivo. Here we focus on the zebrafish morpholino oligonucleotide technology, the (platelet-specific) knockout mouse, and the transplantation of genetically modified human or murine platelet progenitor cells in myelo-conditioned mice. The various strengths and pitfalls of these animal models are illustrated by recent examples from the platelet field. Finally, we highlight the latest developments in genetic engineering techniques and their possible application in platelet research.

E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/β-catenin, PI3K/Akt, Rho GTPase, and NF-κB signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. E-cadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of β-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also E-cadherin-dependent. In addition, the E-cadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implications of E-cadherin expression in these central orchestrators of the immune system.

EGFL7 is a secreted angiogenic factor that is highly conserved in vertebrates. Most secreted angiogenic signaling molecules, including VEGF and fibroblast growth factor-2, are mainly expressed by non-endothelial cell types such as fibroblasts. In contrast, EGFL7 is unique because it is almost exclusively expressed by and acts on endothelial cells. Egfl7 expression is highest when the endothelium is in an active, proliferating state. This factor acts as a chemoattractant for endothelial cells and binds to components of the extracellular matrix. In vivo, Egfl7 is important for regulating tubulogenesis in zebrafish and for controlling vascular patterning and integrity in mice. Its function in blood vessel development is mediated, at least in part, through modulation of Notch signaling. In this review, we summarize the findings that support a role for Egfl7 in developmental and postnatal angiogenesis and describe the EGFL7-signaling pathways that underlie these processes. In addition, we discuss a potential role for EGFL7 in vascular repair and its possible use as a therapeutic target for treatment of hypoxia-induced injury. Finally, we consider EGFL7 action during tumorigenesis and its potential as an antiangiogenic agent.

Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk.

The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead.

Nodular sclerosing Hodgkin lymphoma (NSHL) is a distinct, highly heritable Hodgkin lymphoma subtype. We undertook a genome-wide meta-analysis of 393 European-origin adolescent/young adult NSHL patients and 3315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We identified 3 single nucleotide polymorphisms (SNPs) on chromosome 6p21.32 that were significantly associated with NSHL risk: rs9268542 (P = 5.35 × 10(-10)), rs204999 (P = 1.44 × 10(-9)), and rs2858870 (P = 1.69 × 10(-8)). We also confirmed a previously reported association in the same region, rs6903608 (P = 3.52 × 10(-10)). rs204999 and rs2858870 were weakly correlated (r(2) = 0.257), and the remaining pairs of SNPs were not correlated (r(2) < 0.1). In an independent set of 113 NSHL cases and 214 controls, 2 SNPs were significantly associated with NSHL and a third showed a comparable odds ratio (OR). These SNPs are found on 2 haplotypes associated with NSHL risk (rs204999-rs9268528-rs9268542-rs6903608-rs2858870; AGGCT, OR = 1.7, P = 1.71 × 10(-6); GAATC, OR = 0.4, P = 1.16 × 10(-4)). All individuals with the GAATC haplotype also carried the HLA class II DRB1*0701 allele. In a separate analysis, the DRB1*0701 allele was associated with a decreased risk of NSHL (OR = 0.5, 95% confidence interval = 0.4, 0.7). These data support the importance of the HLA class II region in NSHL etiology.

An important mediator of cytokine signaling implicated in regulation of hematopoiesis is the PI3K/protein kinase B (PKB/c-Akt) signaling module. Constitutive activation of this signaling module has been observed in a large group of leukemias. Because activation of this signaling pathway has been demonstrated to be sufficient to induce hematologic malignancies and is thought to correlate with poor prognosis and enhanced drug resistance, it is considered to be a promising target for therapy. A high number of pharmacologic inhibitors directed against either individual or multiple components of this pathway have already been developed to improve therapy. In this review, the safety and efficacy of both single and dual-specificity inhibitors will be discussed as well as the potential of combination therapy with either inhibitors directed against other signal transduction molecules or classic chemotherapy.

It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.

Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease.

The choice of either induction or postremission therapy for adults with acute myeloid leukemia is still largely based on the "one size fits all" principle. Moreover, pretreatment prognostic parameters, especially chromosome and gene abnormalities, may fail in predicting individual patient outcome. Measurement of minimal residual disease (MRD) is nowadays recognized as a potential critical tool to assess the quality of response after chemotherapy and to plan postremission strategies that are, therefore, driven by the individual risk of relapse. PCR and multiparametric flow cytometry have become the most popular methods to investigate MRD because they have been established as sensitive and specific enough to allow MRD to be studied serially. In the present review, we examine the evidence supporting the appropriateness of incorporating MRD detection into the AML risk assessment process. A comprehensive prognostic algorithm, generated by combining pretreatment cytogenetics/genetics and posttreatment MRD determination, should promote advances in development of personalized therapeutic approaches.

Reversible interactions of glycoconjugates on leukocytes with P- and E-selectin on endothelial cells mediate tethering and rolling of leukocytes in inflamed vascular beds, the first step in their recruitment to sites of injury. Although selectin ligands on hematopoietic precursors have been identified, here we review evidence that PSGL-1, CD44, and ESL-1 on mature leukocytes are physiologic glycoprotein ligands for endothelial selectins. Each ligand has specialized adhesive functions during tethering and rolling. Furthermore, PSGL-1 and CD44 induce signals that activate the β2 integrin LFA-1 and promote slow rolling, whereas ESL-1 induces signals that activate the β2 integrin Mac-1 in adherent neutrophils. We also review evidence for glycolipids, CD43, L-selectin, and other glycoconjugates as potential physiologic ligands for endothelial selectins on neutrophils or lymphocytes. Although the physiologic characterization of these ligands has been obtained in mice, we also note reported similarities and differences with human selectin ligands.

Histocompatibility testing for stem cell and solid organ transplantation has become increasingly complex as newly discovered HLA alleles are described. HLA typing assignments reported by laboratories are used by physicians and donor registries for matching donors and recipients. To communicate effectively, a common language for histocompatibility terms should be established. In early 2010, representatives from Clinical, Registry, and Histocompatibility organizations joined together as the Harmonization of Histocompatibility Typing Terms Working Group to define a consensual language for laboratories, physicians, and registries to communicate histocompatibility typing information. The Working Group defined terms for HLA typing resolution, HLA matching, and a format for reporting HLA assignments. In addition, definitions of verification typing and extended typing were addressed. The original draft of the Definitions of Histocompatibility Typing Terms was disseminated to colleagues from each organization to gain feedback and create a collaborative document. Commentary gathered during this 90-day review period were discussed and implemented for preparation of this report. Histocompatibility testing continues to evolve; thus, the definitions agreed on today probably will require refinement and perhaps additional terminology in the future.

This article reviews the regulation of production of RBCs at several levels. We focus on the regulated expansion of burst-forming unit-erythroid erythroid progenitors by glucocorticoids and other factors that occur during chronic anemia, inflammation, and other conditions of stress. We also highlight the rapid production of RBCs by the coordinated regulation of terminal proliferation and differentiation of committed erythroid colony-forming unit-erythroid progenitors by external signals, such as erythropoietin and adhesion to a fibronectin matrix. We discuss the complex intracellular networks of coordinated gene regulation by transcription factors, chromatin modifiers, and miRNAs that regulate the different stages of erythropoiesis.

Notch signaling pathway regulates many different events of embryonic and adult development; among them, Notch plays an essential role in the onset of hematopoietic stem cells and influences multiple maturation steps of developing lymphoid and myeloid cells. Deregulation of Notch signaling determines several human disorders, including cancer. In the last decade it became evident that Notch signaling plays pivotal roles in the onset and development of T- and B-cell acute lymphoblastic leukemia by regulating the intracellular molecular pathways involved in leukemia cell survival and proliferation. On the other hand, bone marrow stromal cells are equally necessary for leukemia cell survival by preventing blast cell apoptosis and favoring their reciprocal interactions and cross-talk with bone marrow microenvironment. Quite surprisingly, the link between Notch signaling pathway and bone marrow stromal cells in acute lymphoblastic leukemia has been pointed out only recently. In fact, bone marrow stromal cells express Notch receptors and ligands, through which they can interact with and influence normal and leukemia T- and B-cell survival. Here, the data concerning the development of T- and B-cell acute lymphoblastic leukemia has been critically reviewed in light of the most recent findings on Notch signaling in stromal microenvironment.

Myeloid antigen-presenting cells (APCs), regulatory cells, and the HLA-G molecule are involved in modulating immune responses and promoting tolerance. APCs are known to induce regulatory cells and to express HLA-G as well as 2 of its receptors; regulatory T cells can express and act through HLA-G; and HLA-G has been directly involved in the generation of regulatory cells. Thus, interplay(s) among HLA-G, APCs, and regulatory cells can be easily envisaged. However, despite a large body of evidence on the tolerogenic properties of HLA-G, APCs, and regulatory cells, little is known on how these tolerogenic players cooperate. In this review, we first focus on key aspects of the individual relationships between HLA-G, myeloid APCs, and regulatory cells. In its second part, we highlight recent work that gathers individual effects and demonstrates how intertwined the HLA-G/myeloid APCs/regulatory cell relationship is.

Acute and chronic graft-versus-host disease (GVHD) are potentially lethal complications after stem cell transplantation (SCT). Steroids are the appropriate first-line treatment for both. However, if patients do not adequately benefit from steroid therapy, mortality is high and standardized treatment algorithms are lacking. This is mainly because of limited data from prospective, randomized clinical trials. In addition, most of the available treatment options only induce clinical benefits in a limited proportion of patients. Thus, there is an urgent clinical need to develop more potent immunosuppressive treatment strategies for patients suffering from acute or chronic steroid-refractory GVHD while maintaining the graft versus tumor effect to avoid a potential rise in relapse-related mortality. The increasing knowledge about host- as well as donor-derived variables favoring GVHD development and the increasing armamentarium of immune-modulatory agents entering preclinical and clinical research will probably allow more effective treatment of GVHD in the future. This review describes novel developments in the treatment of steroid-refractory GVHD, with a special focus on the rationale behind promising pharmacologic compounds or up-coming cellular therapies.