There appear to be 2 pathways involved in the early pathogenesis of premalignant monoclonal gammopathy of undetermined significance (MGUS) and malignant multiple myeloma (MM) tumors. Nearly half of these tumors are nonhyperdiploid and mostly have immunoglobulin H (IgH) translocations that involve 5 recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factor receptor 3 [FGFR3] and multiple myeloma SET domain [MMSET]), 16q23 (c-maf), and 20q11 (mafB). The remaining tumors are hyperdiploid and contain multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, but infrequently have IgH translocations involving the 5 recurrent loci. Dysregulated expression of cyclin D1, D2, or D3 appears to occur as an early event in virtually all of these tumors. This may render the cells more susceptible to proliferative stimuli, resulting in selective expansion as a result of interaction with bone marrow stromal cells that produce interleukin-6 (IL-6) and other cytokines. There are 5 proposed tumor groups, defined by IgH translocations and/or cyclin D expression, that appear to have differences in biologic properties, including interaction with stromal cells, prognosis, and response to specific therapies. Delineation of the mechanisms mediating MM cell proliferation, survival, and migration in the bone marrow (BM) microenvironment may both enhance understanding of pathogenesis and provide the framework for identification and validation of novel molecular targets.

Alemtuzumab is a monoclonal antibody to CD52 that has activity in T-cell leukemia and lymphoma. This study aims to describe the complications and outcomes of a subset of patients with mycosis fungoides/Sézary syndrome who were treated with alemtuzumab. Four of 8 patients, with no prior history of cardiac problems, developed significant cardiac toxicity (congestive heart failure or arrhythmia) that mostly improved after alemtuzumab discontinuation. The role of this agent in potentially inducing important cardiac side effects is suggested and argues for further investigation.

Epithelial mesenchymal transitions are a remarkable example of cellular plasticity. These transitions are the hallmark of embryo development, are pivotal in cancer progression, and seem to occur infrequently in adult organisms. The reduced incidence of transitions in the adult could result from restrictive functions of the microenvironment that stabilizes adult cell phenotypes and prevents plastic behavior. Multipotential progenitor cells exhibiting a mesenchymal phenotype have been derived from various adult tissues. The ability of these cells to differentiate into all germ layer cell types, raises the question as to whether mesenchymal epithelial transitions occur in the adult organism more frequently than presently appreciated. A series of cytokines are known to promote the transitions between epithelium and mesenchyme. Moreover, several transcription factors and other intracellular regulator molecules have been conclusively shown to mediate these transitions. However, the exact molecular basis of these transitions is yet to be resolved. The identification of the restrictive mechanisms that prevent cellular transitions in adult organisms, which seem to be unleashed in cancerous tissues, may lead to the development of tools for therapeutic tissue repair and effective tumor suppression.

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.

Regulatory T cells participate in immunologic homeostasis by active suppression of inappropriate immune responses. Regulatory T lymphocytes expressing CD4 and CD25 antigens and naturally present in the peripheral blood were the first to be phenotypically characterized. However, their small number and antigen nonspecific suppression has prompted efforts to identify and dissect antigen-specific regulatory T cells. In this review we discuss how antigen-specific regulatory T cells can be identified, the cellular and molecular mechanisms underlying their induction and activity, and the challenges facing their potential clinical application.

Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (ie, C/EBPalpha). Validation of the critical role of certain secondary changes (ie, loss of p53 or C/EBPalpha function) in murine models of CML blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR/ABL and inhibiting or restoring the gene activity gained or lost during disease progression (ie, p53 or C/EBPalpha).

Pregnancy is a hypercoagulable state with an increased thrombotic risk throughout gestation and the postpartum period. Women with thrombophilia may have a further increased risk of placental vascular complications, including pregnancy loss, preeclampsia, intrauterine growth restriction, and placental abruption. Preliminary data suggest that maternal antithrombotic prophylaxis may result in improved gestational outcome. Randomized trials are under way and hopefully will optimize maternal and neonatal outcome.

The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia.

The recent sequencing of a number of genomes has raised the level of opportunities for studies on proteins. This area of research has been described with the all-embracing term, proteomics. In proteomics, the use of mass spectrometric techniques enables genomic databases to be used to establish the identity of proteins with relatively little data, compared to the era before genome sequencing. The use of related analytical techniques also offers the opportunity to gain information on regulation, via posttranslational modification, and potential new diagnostic and prognostic indicators. Relative quantification of proteins and peptides in cellular and extracellular material remains a challenge for proteomics and mass spectrometry. This review presents an analysis of the present and future impact of these proteomic technologies with emphasis on relative quantification for hematologic research giving an appraisal of their potential benefits.

In the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell-depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.

The nuclear factor of activated T cells (NFAT) proteins are a family of transcription factors whose activation is controlled by calcineurin, a Ca2+-dependent phosphatase. Once dephosphorylated, these proteins move to the nucleus where they interact with cofactors to form transcription factor complexes. Inhibition of NFAT proteins by immunosuppressants, such as cyclosporin A (CsA) and FK506, is used clinically to prevent transplant rejection. Although these drugs have revolutionized organ transplantation, their use is associated with severe side effects in other organs in which NFAT proteins are important. One of the signal transducers that controls NFAT activity is Vav1, which is exclusively expressed in the hematopoietic system. Vav1 contains numerous modular domains that enable its function as a guanine exchange factor (GEF) toward RhoGTPases as well as participate in protein-protein interactions. This review focuses on the mechanisms by which Vav1 regulates NFAT through GEF-dependent and -independent cascades, emphasizing the newly assigned role of Vav1 in the regulation of Ca2+ release. Because of its restriction to hematopoietic cell lineages and its importance in the regulation of NFAT, targeting Vav1 and, in particular, its association with other proteins may offer a highly selective means of modifying T-cell behavior, thus allowing the development of more specific immunosuppressive therapies.

Heterogeneity in the clinical behavior of patients with chronic lymphocytic leukemia (CLL) makes it difficult for physicians to accurately identify which patients may benefit from an early or more aggressive treatment strategy and to provide patients with relevant prognostic information. Given the potential efficacy of newer therapies and the desire to treat patients at "optimum" times, it is more important than ever to develop sensitive stratification parameters to identify patients with poor prognosis. The evolution of risk stratification models has advanced from clinical staging and use of basic laboratory parameters to include relevant biologic and genetic features. This article will review the dramatic progress in prognostication for CLL and will propose statistical modeling techniques to evaluate the utility of these new measures in predictive models to help determine the optimal combination of markers to improve prognostication for individual patients. This discussion will also elaborate which markers and tools should be used in current clinical practice and evaluated in ongoing clinical trials.

GATA-1 is the founding member of a transcription factor family that regulates growth and maturation of a diverse set of tissues. GATA-1 is expressed primarily in hematopoietic cells and is essential for proper development of erythroid cells, megakaryocytes, eosinophils, and mast cells. Although loss of GATA-1 leads to differentiation arrest and apoptosis of erythroid progenitors, absence of GATA-1 promotes accumulation of immature megakaryocytes. Recently, we and others have reported that mutagenesis of GATA1 is an early event in Down syndrome (DS) leukemogenesis. Acquired mutations in GATA1 were detected in the vast majority of patients with acute megakaryoblastic leukemia (DS-AMKL) and in nearly every patient with transient myeloproliferative disorder (TMD), a "preleukemia" that may be present in as many as 10% of infants with DS. Although the precise pathway by which mutagenesis of GATA1 contributes to leukemia is unknown, these findings confirm that GATA1 plays an important role in both normal and malignant hematopoiesis. Future studies to define the mechanism that results in the high frequency of GATA1 mutations in DS and the role of altered GATA1 in TMD and DS-AMKL will shed light on the multistep pathway in human leukemia and may lead to an increased understanding of why children with DS are markedly predisposed to leukemia.

Congenital thrombocytopenias, once considered rare and obscure conditions, are today recognized with increasing frequency, especially due to the measurement of platelet number as part of routine blood testing. The clinical spectrum of congenital thrombocytopenia ranges from severe bleeding diatheses, recognized within the first few weeks of life, to mild conditions that may remain undetected even in adulthood. For the latter group of diseases, distinguishing between inherited (primary) and acquired (secondary) thrombocytopenia, especially immune thrombocytopenia purpura (ITP), is essential to avoid unnecessary and potentially harmful treatments. In this review, the congenital thrombocytopenia syndromes are discussed with specific attention focused on diagnostic criteria, clinical presentations, genetic etiology, and current medical management. The mutated genes responsible for each syndrome are reviewed as well as the potential implications for using gene therapy or gene repair in the future.

Autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.

There is a strong graft-versus-leukemia (GVL) effect of allogeneic stem cell transplantation (SCT) due to elimination of tumor cells by alloimmune effector lymphocytes. When leukemia relapses after allogeneic SCT, donor lymphocyte transfusions (DLTs) can induce sustained remissions in some patients. This review summarizes the current status on clinical use of DLT, the basis of GVL reactions, problems associated with this therapy, and new strategies to improve DLT. Several multicenter surveys demonstrated that the GVL effect of DLT is most effective in chronic myelogenous leukemia (CML), whereas it is less pronounced in acute leukemia and myeloma. Cytokine stimulation to induce differentiation of myeloid progenitor cells or to up-regulate costimulatory molecules on tumor cells may improve the efficacy of DLT. Infections and graft-versus-host disease (GVHD) are major complications of DLT. Control of GVHD may be improved using suicide gene-modified T cells for DLT, allowing T-cell elimination if severe GVHD develops. Hopefully, in the future, GVL effect can be separated from GVHD through adoptive transfer of selected T cells that recognize leukemia-specific antigens or minor histocompatibility antigens, which are expressed predominantly on hematopoietic cells, thereby precluding attack of normal tissues. In patients with leukemia and lymphomas with fast progression, tumor growth may outpace development of effector T cells. Here it may be preferable to select stem cell transplant donors with HLA-mismatches that allow alloreactive natural killer cells, which appear early after transplantation, to retain their cytolytic function. New approaches for adoptive immune therapy of leukemia, which promise a better prognosis for these patients, are being developed.

Numerous studies have examined the outcomes of infants born to mothers with idiopathic thrombocytopenic purpura (ITP). Fewer studies have discussed the morbidity of obstetric patients with ITP. We describe a retrospective study of 92 women with ITP during 119 pregnancies over an 11-year period. Most women had thrombocytopenia during pregnancy. At delivery, women in 98 pregnancies (89%) had platelet counts lower than 150 x 109/L; most had mild to moderate thrombocytopenia. For many, the pregnancy was uneventful; however, women had moderate to severe bleeding in 25 pregnancies (21.5%). Women in 37 pregnancies (31.1%) required treatment to increase platelet counts. During delivery, 44 women (37.3%) received epidural analgesia without complications, with most having a platelet count between 50 and 149 x 109/L. Most deliveries (82.4%) were vaginal. Bleeding was uncommon at delivery. Infant platelet counts at birth ranged from 12 to 436 x 109/L; 25.2% of infants had platelet counts lower than 150 x 109/L, and 9% had platelet counts lower than 50 x 109/L. Eighteen infants (14.6%) required treatment for hemostatic impairment. Two fetal deaths occurred. One was caused by hemorrhage. ITP in pregnancy carries a low risk, but mothers and infants may require therapy to raise their platelet counts.

Congenital dyserythropoietic anemia type II (CDA II) is the most frequent type of congenital dyserythropoietic anemia. More than 200 cases have been described, but with the exception of a report by the International CDA II Registry, these reports include only small numbers of cases and no data on the lifetime evolution of the disease. Since 1967, we were able to follow 48 cases of CDA II from 43 families for up to 35 years. All patients exhibit chronic anemia of variable severity requiring regular red cell transfusions only in a minority of children; 60% developed gallstones before the age of 30 years, and 16 patients had cholecystectomy between 8 and 34 years of age. Iron overload was a frequent complication. In 16 cases, iron depletion started between 7 and 36 years. Three patients died from secondary hemochromatosis. Splenectomy, performed in 22 cases, led to moderate increases in hemoglobin values and eliminated the need for transfusions but did not prevent further iron loading. The current recommendation is to consider splenectomy if the anemia compromises patients' performance, and to manage iron overload according to the guidelines derived from patients with thalassemia.

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth across a wide range of malignant phenotypes. Many hematologic malignancies appear to be reasonable disease targets, in that they express relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), AKT, and others that may depend on farnesyl protein transferase (FTase) activity to promote proliferation and survival. A host of phase 1 trials have been recently launched to assess the applicability of FTIs in hematologic malignancies, many of which demonstrate effective enzyme target inhibition, low toxicity, and some clinical responses. As a result, phase 2 trials have been initiated in a variety of hematologic malignancies and disease settings to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.

Results of unrelated cord blood transplantation (UCBT) in childhood acute myeloid leukemia (AML) have not been previously reported. We analyzed 95 children receiving UCB transplants for AML (20 in first complete remission [CR1], 47 in CR2, and 28 in more advanced stage). Poor prognosis cytogenetic abnormalities were identified in 29 cases. Most patients received a 1 or 2 HLA antigens-mismatched UCB transplants. The median number of collected nucleated cells (NCs) was 5.2 x 107/kg. Cumulative incidence (CI) of neutrophil recovery was 78% +/- 4%, acute graft-versus-host disease (GVHD) was 35% +/- 5%, and 100-day transplantation-related mortality (TRM) was 20% +/- 4%. In multivariable analysis, a collected NC dose higher than 5.2 x 107/kg was associated with a lower 100-day TRM. The 2-year CI of relapse was 29% +/- 5% and was associated with disease status. The 2-year leukemia-free survival (LFS) was 42% +/- 5% (59% +/- 11% in CR1, 50% +/- 8% in CR2, and 21% +/- 9% for children not in CR). Children with poor prognosis cytogenetic features had similar LFS compared with other patients (44% +/- 11% vs 40% +/- 8%). In CR2, LFS was not influenced by the length of CR1 (53% +/- 11% in CR1 < 9.5 months compared with 50% +/- 12% in later relapses). We conclude that UCBT is a therapeutic option for children with very poor-prognosis AML and who lack an HLA-identical sibling.