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1.  N-cadherin impedes proliferation of the multiple myeloma cancer stem cells 
Multiple myeloma (MM) is an incurable malignancy of the plasma cells localized to the bone marrow. A rare population of MM cancer stem cells (MM-CSCs) has been shown to be responsible for maintaining the pull of residual disease and to contribute to myeloma relapse. The stem cells are found in a bone marrow niche in contact with the stromal cells that are responsible for maintaining the proliferative quiescence of the MM-CSC and regulate its self-renewal and differentiation decisions. Here we show that both MM and bone marrow stromal cells express N-cadherin, a cell-cell adhesion molecule shown to maintain a pool of leukemic stem cells. Inhibition of N-cadherin using a neutralizing antibody led to an increase in the MM cell proliferation. A decrease in MM cell adhesion to the bone marrow stroma was observed in the first 24 hours of co-culture followed by a 2.3-30-fold expansion of the adherent cells. Moreover, inhibition of N-cadherin led to a 4.8-9.6-fold expansion of the MM-CSC population. Surprisingly, addition of the N-cadherin antagonist peptide resulted in massive death of the non-adherent MM cells, while the viability of the adherent cells and MM-CSCs remained unaffected. Interestingly, the proliferative effects of N-cadherin inhibition were not mediated by the nuclear translocation of β-catenin. Taken together, our findings demonstrate the crucial role of N-cadherin in regulating MM cell proliferation and viability and open an interesting avenue of investigation to understand how structural modifications of N-cadherin can affect MM cell behavior. Our findings suggest that targeting N-cadherin may be a useful therapeutic strategy to treat MM in conjunction with an agent that has anti-MM-CSC activity.
PMCID: PMC3875273  PMID: 24396705
Multiple myeloma; cancer stem cells; N-cadherin
2.  Chronic myelogenous leukemia after postoperative adjuvant S-1 therapy for rectal cancer: a case report 
We report a case in which chronic myelogenous leukemia (CML) developed after postoperative adjuvant S-1 therapy for rectal cancer. A 56-year-old man was diagnosed with rectal adenocarcinoma, which was treated with abdominoperineal resection followed by a year of adjuvant S-1 therapy. At 39 postoperative months, he was diagnosed with CML. Although it remains unclear that CML that develops after treatment involving cytotoxic agents is treatment-related, clinicians should be aware of the possibility of CML developing after S-1 therapy.
PMCID: PMC3875274  PMID: 24396706
Chronic myelogenous leukemia; rectal cancer; fluoropyrimidine; S-1
3.  Granulocytic sarcoma: a systematic review 
Granulocytic sarcoma also called myeloid sarcoma is an extramedullary tumor of immature granulocytic cells. It is a rare entity, and mostly accompanied by acute myeloid leukemia. It is observed during the course of myeloproliferative disorders especially in chronic myeloid leukemia and myelodysplastic syndromes. In some rare circumstances, it is detected before clinical signs of leukemia or other diseases. When the bone marrow biopsy reveals no other hematologic malignancies, the granulocytic sarcoma is described as nonleukemic, primary or isolated. It is observed at any part of the body but the most common locations are soft tissues, bone, peritoneum and lymph nodes. Presenting signs or symptoms are mainly due to mass effect of the tumor and dysfunction of the organ, or the tissue that is affected. The diagnosis is performed by biopsy of the tumor. The tumor consists of immature granulocytic cells, which could be documented by H&E, immunohistochemistry, and flow cytometric methods. Fluorescence in-situ hybridization and molecular analysis are also performed. The optimal time and type of treatment is not clear. Surgery could be an option especially for tumors, which cause organ dysfunction and/or obstruction. Systemic treatment should be considered in all patients because without systemic treatment, relapses and progression to acute myeloid leukemia is the ultimate fate of the disease in many cases. Cytarabine-containing remission-induction chemotherapies have been the most applied therapeutic strategies, but it is not clear whether the consolidation therapies are required or not, and what kind of regimens are appropriate. The role of hematopoietic stem cell transplantation (HSC) as a consolidation regimen is not clear, but, after the relapse of the disease with or without bone marrow involvement, HSC transplantation should be considered in suitable patients after the reinduction performed by AML chemotherapies. There is only limited data about the role of radiotherapy in these patients. It could be used in patients with relapsed disease, organ dysfunction which should be quickly relieved and inadequate response to chemotherapy. The effect of radiotherapy on overall survival is not known. New prospective studies and clinical trials are needed to generate guidelines for the treatment of primary granulocytic sarcomas.
PMCID: PMC3875275  PMID: 24396704
Granulocytic sarcoma; treatment; chemotherapy; leukemia
4.  The Epstein-Barr virus microRNA BART11-5p targets the early B-cell transcription factor EBF1 
Epstein-Barr virus (EBV) is a ubiquitous B-cell trophic herpesvirus associated with a variety of histologically diverse B-cell lymphomas, each associated with specific viral-latency gene expression programs. Initial infection drives resting B-cells to differentiate via an atypical germinal centre reaction into memory B-cells, where the virus resides in a latent state. The mechanisms that underpin this process have yet to be fully elucidated. EBV expresses more than 40 microRNAs (miRNAs). The alternatively spliced BamHI A rightward transcripts (BARTs) are the template for two large miRNA clusters (BARTs A and B), that comprise the majority of all known EBV-miRNAs. Although BART-miRNAs are abundantly expressed in all latency programs, few BART-miRNA targets have been identified and their function is poorly understood. The early B-cell factor 1 (EBF1) was identified using bioinformaticss analysis as a novel target of EBV-miRNA BART11-5p, encoded by BART cluster B. EBF1 is an important B-cell transcription factor that regulates many B-cell specific genes including Pax5, BCR and CD40 and is critical for germinal centre formation. Using luciferase reporter assays and a series of BART-constructs, we confirmed silencing via the EBF1 3’ untranslated region (UTR) and identified the target site as 2137-2159 bp after the stop codon. Results were confirmed following transfection of a BART11-5p mimic, which was able to silence via the predicted target site. Our findings highlight a potential role of BART-miRNAs in the regulation of B-cell differentiation.
PMCID: PMC3755520  PMID: 23997984
EBV; microRNA; BamHI A rightward transcripts; early B-cell transcription factor; B-cell
5.  Changes in molecular biology of chronic myeloid leukemia in tyrosine kinase inhibitor era 
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by a reciprocal translocation between long arms of chromosomes 9 and 22 t(9;22) that generates the BCR-ABL fusion gene. If left untreated, newly diagnosed chronic phase CML patients finally progress to accelerated and blastic phase. After the introduction of tyrosine kinase inhibitors (TKIs), treatment strategies of CML changed dramatically. However, the development of resistance to TKIs started to create problems over time. In this review, the current information about CML biology before and after imatinib mesylate treatment is summarized.
PMCID: PMC3755521  PMID: 23997982
Chronic myeloid leukemia; moleculer biology; imatinib mesylate
6.  Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC) 
Background: Several studies revealed that MSC from human bone marrow can downregulate graft-versus-host disease (GVHD) after allogeneic HSCT. Methods: Herein we present 50 patients with acute GVHD who got 74 (1-4) MSC infusions for 54 separate episodes of aGVHD. Results: aGVHD was defined as steroid resistant grade IV aGVHD in 42 cases. The major presentation was gastrointestinal GVHD; two (n=18) or more (n=21) systems were involved in the majority of cases. The 1st infusion with MSC was given on day +27 (range, 1 to 136); d+45 (range, +11 to +150) post diagnosis of aGVHD and HSCT, respectively. In 2/3 of the cases treatment was performed with frozen stocked MSCs; in 62 cases early passages (1-3) were used. The median number of infused cells was 1.14±0.47 million per kg in the first injection and up to 4.27 (1.70±1.10) millions in total. The two patients with aggressive liver GVHD received MSCs injections intra hepatic arteries without changes of blood flow or evidence cytolysis, but also without a visible effect. Disease free survival at 3.6 years was 56%. We observed better overall survival in patients with GVHD grade < 4, in responders to the 1st treatment with MSC, and in pediatric group. The multivariate analysis demonstrated independent influence on survival of initial response and younger age. There were no immediate or late toxicity or side effects. Conclusion: Injection of MSCs seems to be a promising and safe treatment of GVHD. The encouraging results obviously should be confirmed in a randomized prospective study.
PMCID: PMC3755522  PMID: 23997985
Mesenchymal stromal cells (MSC); mesenchymal stem cells; hematopoietic stem cell transplantation; graft versus host disease; steroid resistance
7.  Costs and quality of life in patients with myelodysplastic syndromes 
Myelodysplastic syndromes (MDS) encompass a range of myeloid neoplasms characterised by a defect in haematopoietic stem cell maturation, resulting in peripheral cytopenias. As a major consequence, most MDS patients become anaemic, so as to require red blood cell transfusions. To investigate the costs and the impact on quality of life (QOL) of MDS-separately in transfusion-independent (TI) and -dependent (TD) patients-a literature search was conducted. From Medline and Embase, 742 studies were identified, of which 17 were considered eligible. Total medical costs per patient/year range from $ 9,840 to $ 19,811 for the TI condition and from $ 29,608 to $ 51,066 in the TD condition, more than doubling when moving from the former condition to the latter. With regard to QOL, in the transition from TI to TD, QOL could be reduced by half depending on the studies. The TD condition negatively impacts on costs and the QOL of patients with MDS. Therapeutic strategies that reduce transfusion dependence may lead to broad benefits for patients and the community.
PMCID: PMC3755523  PMID: 23997987
Myelodysplastic syndromes; anemia; transfusion dependence; quality of life; medical costs
8.  Detection of immune suppressive neutrophils in peripheral blood samples of cancer patients 
Neutrophils provide first-line defense against infections and are potent effectors in innate and adaptive immunity. Recently neutrophils have been shown to play important roles in multiple antitumor reactions. A subset of mature neutrophils in human systemic inflammation has been identified as a unique circulating population of myeloid cells, which is capable of inhibiting T cell responses. These neutrophils show unique immunophenotype (CD11c bright/CD62L dim/CD11b bright/CD16 bright). This study reports detection of mature neutrophils with similar immunophenotype in the peripheral blood samples of cancer patients using flow cytometry analysis. This population of neutrophils is not detected in peripheral blood samples of normal controls. Thus this finding suggests the involvement of mature neutrophils in antitumor immunity.
PMCID: PMC3755524  PMID: 23997986
Neutrophils; immunosuppressive; cancer; CD62L
9.  Tailoring of chronic lymphatic leukemia therapy 
Chronic lymphocytic leukemia (CLL) remains an incurable disease, with all patients who require therapy destined to relapse and understanding of the pathophysiology of chronic lymphocytic leukemia has advanced significantly. It is now clear that chronic lymphocytic leukemia is a relatively proliferative disorder that requires the help of its microenvironment to be maintained and to progress. The stimulation of the chronic lymphatic leukemia cell occurs in most, if not all, patients through antigen stimulation via the B cell receptors. In addition, there is now a appreciation of the role of the p53 pathway leading to chemoresistance and the elucidation of the molecular and intracellular signaling mechanisms of disease is just beginning to facilitate the development of several targeted small molecules that promise to revolutionize the treatment of Chronic lymphocytic leukemia.
PMCID: PMC3755525  PMID: 23997983
Chronic lymphocytic leukemia; pathophysiology; target therapy
10.  Romiplostim for delayed platelet recovery and secondary thrombocytopenia following allogeneic stem cell transplantation 
Delayed recovery of platelet count post allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been associated with worse transplant outcomes. Thrombopoietic agents have been successfully used in immune mediated thrombocytopenia or thrombocytopenia from bone marrow failure syndromes; however, the experience regarding their use after allo-HSCT is limited. Here we report on the safety and efficacy of romiplostim used in 3 consecutive patients with thrombocytopenia post allogeneic transplantation. Two patients had prolonged platelet recovery due to poor graft function while one had secondary failure of platelet recovery, likely immune mediated, post transplantation. Successful use of such agents post-transplant may improve platelet recovery, decrease rates of complications and potentially improve outcomes.
PMCID: PMC3755526  PMID: 23997988
Post-transplant thrombocytopenia; romiplostim; allogeneic hematopoietic stem cell transplantation
11.  Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release 
Background: Platelet microparticles (PM) are the most abundant cell-derived microparticles in the blood, and accumulate in thrombo-inflammatory diseases. Platelets produce PM upon aging via an apoptosis-like process and by activation with strong agonists. We previously showed that long-term treatment of monocytic cells with apoptosis-induced PM (PMap) promotes their differentiation into resident macrophages. Here we investigated shorter term effects of various types of PM on monocyte signalling and function. Methods and results: Flow cytometry and scanning electron microscopy revealed that PM formed upon platelet aging (PMap) or ultra-sonication (PMsonic) expressed activated αIIbβ3 integrins and tended to assemble into aggregates. In contrast, PM formed upon platelet activation with thrombin (PMthr) or Ca2+ ionophore (PMiono) had mostly non-activated αIIbβ3 and little aggregate formation, but had increased CD63 expression. PM from activated and sonicated platelets expressed phosphatidylserine at their surface, while only the latter were enriched in the receptors CD40L and CX3CR1. All PM types expressed P-selectin, interacted with monocytic cells via this receptor, and were internalised into these cells. The various PM types promoted actin cytoskeletal rearrangements and hydrogen peroxide production by monocytic cells. Markedly, both aging- and activation-induced PM types stimulated the phosphoinositide 3-kinase/Akt pathway, suppressing apoptosis induced by several agonists, in a P-selectin-dependent manner. On the other hand, the PM types differentially influenced monocyte signalling in eliciting Ca2+ fluxes (particularly PMap) and in releasing secondary mediators (complement factor C5a with PMap, and pro-inflammatory tumour necrosis factor-α with PMthr). Conclusions: In spite of their common anti-apoptotic potential via Akt activation, aging- and activation-induced PM cause different Ca2+ signalling events and mediator release in monocytic cells. By implication, aging and activated platelets may modulate monocyte function in different way by the shedding of different PM types.
PMCID: PMC3649808  PMID: 23675563
Aging; apoptosis; microparticles; monocytes; platelet activation; tumour necrosis factor
12.  A rare der(Y)t(Y;1)(q12;q12) in a patient with post-polycythemic myelofibrosis: a case report 
We describe a case of post-polycythemic myelofibrosis harboring der(Y)t(Y;1)(q12;q12). The patient was a 69-year-old man and was initially diagnosed with polycythemia vera. During the clinical course of his condition, the polycythemia developed into myelofibrosis. Chromosome analysis detected der(Y)t(Y;1)(q12;q12). We discuss the association between der(Y)t(Y;1)(q11~12;q12~21) and tumorigenesis along with a review of literature.
PMCID: PMC3649809  PMID: 23675569
Post-polycythemic myelofibrosis; der(Y)t(Y;1)(q12;q12); chromosomal abnormality
13.  Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian competence network (AUCNM) 
Systemic mastocytosis (SM) is a hematopoietic neoplasm characterized by pathologic expansion of tissue mast cells in one or more extracutaneous organs. In most children and most adult patients, skin involvement is found. Childhood patients frequently suffer from cutaneous mastocytosis without systemic involvement, whereas most adult patients are diagnosed as suffering from SM. In a smaller subset of patients, SM without skin lesions develops which is a diagnostic challenge. In the current article, a diagnostic algorithm for patients with suspected SM is proposed. In adult patients with skin lesions and histologically confirmed mastocytosis in the skin (MIS), a bone marrow biopsy is recommended regardless of the serum tryptase level. In adult patients without skin lesions who are suffering from typical mediator-related symptoms, the basal serum tryptase level is an important diagnostic parameter. In those with slightly elevated tryptase (15-30 ng/ml), additional non-invasive investigations, including a KIT mutation analysis of peripheral blood cells and sonographic analysis, is performed. In adult patients in whom i) KIT D816V is detected or/and ii) the basal serum tryptase level is clearly elevated (> 30 ng/ml) or/and iii) other clinical or laboratory features are suggesting the presence of occult mastocytosis, a bone marrow biopsy should be performed. In the absence of KIT D816V and other indications of mastocytosis, no bone marrow investigation is required, but the patient’s course and the serum tryptase levels are examined in the follow-up.
PMCID: PMC3649810  PMID: 23675567
Mastocytosis; tryptase; KIT D816V; diagnostic algorithm; staging
14.  Immune surveillance and lymphoid malignancy in immunocompromised host 
Immune surveillance is a dynamic process that involves an intact immune system to identify and protect the host against tumor development. The increased understanding of the genetics, infections and hematological malignancies in congenital immune deficiency states supports the concept that impaired T cells and Natural-killer/T cells leads to B-cell lymphoma. Furthermore, severe combined immunodeficient mice are prone to spontaneous tumor development and therefore serve as experimental models. Here we discuss the acquired conditions and mechanisms involved in dysregulation of the immune system that lead to lymphoma. Preemptive strategies to improve immune regulation and response and restore a competent immune system may lead to a decrease in lymphoid malignancies.
PMCID: PMC3649811  PMID: 23675561
Lymphoma; immune surveillance; immune deficiency
15.  MyD88 is involved in myeloid as well as lymphoid hematopoiesis independent of the presence of a pathogen 
MyD88 was originally described as a primary response gene up-regulated during myeloid differentiation after IL-6 induction. Later, MyD88 was shown to be a key molecule necessary for IL1, IL18 and Toll-like receptor signaling. Since these receptors recognize abundantly produced cytokines during infection or molecular patterns of pathogens, MyD88 itself was suggested to be an important regulator of the first line of defense against invading pathogens, including the differentiation and maturation of myeloid cells. Here we describe that MyD88 is important for early and late hematopoietic events that occur independently of antigen under steady-state conditions. In MyD88-deficient mice the earliest alteration in hematopoiesis was found at the level of long-term hematopoietic stem cells. Moreover, we found that MyD88 influences not only the development of the myeloid lineage but also the differentiation of B cells. The B cell defect observed in Btk-deficient mice is further enhanced when both molecules, Btk and MyD88, are not expressed. Therefore, MyD88 affects myeloid as well as lymphoid hematopoiesis. Since Btk and MyD88 deficiencies influence differentially myeloid and lymphoid development, both molecules seem to act in different signaling pathways important for appropriate developmental events during myelo- and lymphopoiesis.
PMCID: PMC3649812  PMID: 23675564
MyD88; Btk; hematopoiesis; myelopoiesis; lymphopoiesis
16.  Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus 
Patients over age 60 comprise the majority of those diagnosed with acute myeloid leukemia (AML), but treatment approaches in this population are variable, with many uncertainties and controversies. Our group conducted a literature review to summarize the latest information and to develop a consensus document with practical treatment recommendations. We addressed five key questions: selection criteria for patients to receive intensive induction chemotherapy; optimal induction and post-remission regimens; allogeneic hematopoietic stem cell transplantation (HSCT); treatment of patients not suitable for induction chemotherapy; and treatment of patients with prior hematological disorders or therapy-related AML. Relevant literature was identified through a PubMed search of publications from 1991 to 2012. Key findings included the recognition that cytogenetics and molecular markers are major biologic determinants of treatment outcomes in the older population, both during induction therapy and following HSCT. Although disease-specific and patient-specific risk factors for poor outcomes are more common in the older population, age is not in itself sufficient grounds for withholding established treatments, including induction and consolidation chemotherapy. The role of HSCT and use of hypomethylating agents are discussed. Finally, suggested treatment algorithms are outlined, based on these recommendations.
PMCID: PMC3649813  PMID: 23675565
Acute myeloid leukemia; chemotherapy; cytogenetics; prognosis; hematopoietic stem cell transplantation; hypomethylating agent
17.  Absence of BRAF exon 15 mutations in multiple myeloma and Waldenström’s macroglobulinemia questions its validity as a therapeutic target in plasma cell neoplasias 
Purpose: Recent whole genome and/or exome sequencing in a cohort of 32 Multiple Myeloma (MΜ) patients reported the incidence of BRAF mutations at 4%, while in another exome sequencing study, BRAF mutations were reported in up to 13% of cases tested. We ran a confirmatory study by using High Resolution Melting Analysis (HRMA), which is a low-cost, straightforward and sensitive screening test for detection of BRAF exon 15 mutations in MM and Waldenström’s macroglobulinemia (WM) patients, in order to investigate their incidence in every day clinical practice. We considered this investigation to be of clinical relevance following the recent emergence of potent anti-BRAF compounds. Patients and Methods: We used genomic DNA isolated from 31 bone marrow aspirates obtained from 25 MM patients and 3 patients with WM (14 female; 14 male) who signed an informed consent. Patients’ median age was 69 years (range 43-86) and median follow-up time was 45 months. Myeloma subtypes were as follows: 7 IgGκ, 6 IgGλ, 7 IgAλ, 4 IgAλ and 1 non-secretory. The bone marrow plasma cells ranged from 12 to 100% (mean/median value 45%). By International Staging System (ISS) 9/25 patients were stage Ι, 6/25 stage ΙΙ, 7/25 stage ΙΙΙ, while in 3 cases staging information was missing. In 3 MM cases matched paired samples at diagnosis and at relapse were also available. DNA samples were screened using HRMA. HRMA results were confirmed by subsequent ds-bi-directional sequencing (Sanger method) for somatic mutations in exon 15 of BRAF. Results: At a limit of detection ≥2.5% mutant allelic content by HRMA, we did not detect any BRAF mutations in exon 15 in any of our 31 samples. Conclusions: By using HRMA we do not confirm previously reported results. Lack of detection of BRAF exon 15 mutations in our MM and WM series may be related to different sensitivity of the assays used and/or the relatively small sample size. In any case, we consider that existing data should be taken into account when considering the clinical development of BRAF inhibitors in plasma cell neoplasms.
PMCID: PMC3649814  PMID: 23675568
Multiple myeloma; BRAF; mutation; WaldenstrÖm’s macroglobulinemia; high resolution melting analysis
18.  Understanding basic steps to hematopoietic stem cell transplantation evaluation 
We are celebrating one millionth transplant in year 2013! With continued improvement in hematopoietic cell transplantation (HCT) outcome, the indications for HCT continue to grow. Furthermore the sources of stem cells and the number of suitable matches are expanding. At the same time, modified transplantation regimens have facilitated safer procedures despite increase in patient’s age and comorbidies. In the current era, any patient indicated for HCT has a stem cell source and therefore steps to HCT and coordinated pre-transplant care is an integral part of management to improve transplant outcome. This review discusses our approach to the transplant evaluation process and this article will serve as a valuable tool for primary care physicians and referring hematologists/oncologists.
PMCID: PMC3649815  PMID: 23675562
Transplantation; hematological malignancies; preparation; evaluation
19.  Refinement of IKZF1 recombination hotspots in pediatric BCP-ALL patients 
Chromosomal translocations resulting in chimeric fusion genes are prototypic for pediatric leukemia patients. The most known fusions are ETV6-RUNX1 or BCR-ABL1 in B-cell progenitor (BCP)-ALL, and rearrangements of MLL in pediatric ALL and AML. Genome-wide sequencing projects have revealed additional, recurrent gene mutations in B cell malignancies. One of these mutations comprises the IKZF1 gene, encoding the IKAROS transcription factor which is one of the essential transcription factors driving lymphoid development. IKZF1 deletions were first identified by SNP arrays in ALL patients, and later identified with a high prevalence in BCR-ABL1+ patients. IKZF1 deletions turned out to be an independent prognostic marker associated with a poor outcome. Here, we characterized IKZF1 deletions in pediatric BCP-ALL patients by combining MLPA mapping experiments with long distance inverse PCR. The aim of our study was also to compare existing methods with our approach. Our attempt confirmed many of the existing data but revealed a more complex pattern of recombination sites, including a total of 4 recombination hotspots. This extended knowledge was translated into a novel, multiplex PCR assay that allows to perform IKZF1 deletion analyses by using a 2-tube PCR approach.
PMCID: PMC3649816  PMID: 23675566
Childhood leukemia; cancer genetics; gene deletion; IKAROS; IKZF1; leukemia markers
20.  Regulation of innate immunity by extracellular nucleotides 
Extracellular ATP (eATP) is the most abundant among extracellular nucleotides and is commonly considered as a classical danger signal, which stimulates immune responses in the presence of tissue injury. In fact, increased nucleotide concentration in the extracellular space is generally closely associated with tissue stress or damage. However non-lytic nucleotide release may also occur in many cell types under a variety of conditions. Extracellular nucleotides are sensed by a class of plasma membrane receptors called P2 purinergic receptors (P2Rs). P2 receptors are expressed by all immunological cells and their activation elicits different responses. Extracellular ATP can act as an initiator or terminator of immune responses being able to induce different effects on immune cells depending on the pattern of P2 receptors engaged, the duration of the stimulus and its concentration in the extracellular milieu. Millimolar (high) concentrations of extracellular ATP, induce predominantly proinflammatory effects, while micromolar (low) doses exert mainly tolerogenic/immunosuppressive action. Moreover small, but significant differences in the pattern of P2 receptor expression in mice and humans confer diverse capacities of ATP in regulating the immune response.
PMCID: PMC3555188  PMID: 23358447
Extracellular nucleotides; P2 purinergic receptors; extracellular ATP; innate immunity
21.  Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander? 
Regulatory T (Treg) cells are now under extensive investigation in chronic lymphocytic leukemia (CLL). This small subset of T-cells has been, in fact, considered to be involved in the pathogenesis and progression of CLL. However, whether Treg dysregulation in CLL plays a key role or it rather represents a simple epiphenomenon is still matter of debate. In the former case, Treg cells could be appealing for targeting therapies. Finally, Treg cells have also been proposed as a prognostic indicator of the disease clinical course.
PMCID: PMC3555189  PMID: 23358515
Tregs; chronic lymphocytic leukemia; prognosis
22.  Gene mutations and molecularly targeted therapies in acute myeloid leukemia 
Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations.
PMCID: PMC3555190  PMID: 23358589
Acute myeloid leukemia; targeted therapy; mutation; FLT3; NPM1; CEBPA; JAK2
23.  Repeated treatment with high dose cyclophosphamide for severe autoimmune diseases 
High dose cyclophosphamide (HiCY) without stem cell rescue has been shown to induce remissions in patients with severe autoimmune disorders (SADS). However, up to 80% of these patients ultimately relapse. Here we review the outcomes of seven patients treated with two cycles and one patient treated with three cycles of HiCY. The diseases re-treated were scleroderma, multiple sclerosis, three patients with severe aplastic anemia (SAA), and three patients with myasthenia gravis (MG). All but two patients with SAA had received standard immunomodulatory therapy for their disease up front and had been refractory. All patients had complete hematologic recovery. Overall survival in this cohort was 100%. All patients relapsed after the initial cycle but event free survival thereafter was 93.3%. All are still in remission except two MG patients, one of whom relapsed after a severe GI infection requiring hospitalization, and the other relapsed 3 years after the second treatment and she did not respond to the third treatment. This shows that HiCY can be safely re-administered in patients with SAA and refractory SADS. The quality and duration of second remissions appears to be equal or superior to the first remission.
PMCID: PMC3555191  PMID: 23358715
Autoimmunity; cyclophosphamide; severe autoimmune diseases
24.  Suppression of STAT5A and STAT5B chronic myeloid leukemia cells via siRNA and antisense-oligonucleotide applications with the induction of apoptosis 
Signal transducers and activators of transcription (STAT) proteins function in the JAK/STAT signaling pathway and are activated by phosphorylation. As a result of this signaling event, they affect many cellular processes including cell growth, proliferation, differentiation, and survival. Increases in the expressions of STAT5A and STAT5B play a remarkable role in the development of leukemia in which leukemic cells gain uncontrolled proliferation and angiogenesis ability. At the same time, these cells acquire ability to escape from apoptosis and host immune system. In this study, we aimed to suppress STAT-5A and -5B genes in K562 CML cells by siRNA transfection and antisense oligonucleotides (ODN) targeting and then to evaluate apoptosis rate. Finally, we compared the transfection efficiencies of these approaches. Quantitative RT-PCR and Western blot results indicated that STAT expressions were downregulated at both mRNA and protein levels following siRNA transfection. However, electroporation mediated ODN transfection could only provide limited suppression rates at mRNA and protein levels. Moreover, it was displayed that apoptosis were significantly induced in siRNA treated leukemic cells as compared to ODN treated cells. As a conclusion, siRNA applications were found to be more effective in terms of gene silencing when compared to ODN treatment based on the higher apoptosis and mRNA suppression rates. siRNA application could be a new and alternative curative method as a supporting therapy in CML patients.
PMCID: PMC3555192  PMID: 23358828
Chronic myeloid leukemia; K562; STAT5; siRNA knockdown; antisense oligonucleotides; apoptosis
25.  Function of Ikaros as a tumor suppressor in B cell acute lymphoblastic leukemia 
The Ikaros transcription factor is crucial for many aspects of hematopoiesis. Loss of function mutations in IKZF1, the gene encoding Ikaros, have been implicated in adult and pediatric B cell acute lymphoblastic leukemia (B-ALL). These mutations result in haploinsufficiency of the Ikaros gene in approximately half of the cases. The remaining cases contain more severe or compound mutations that lead to the generation of dominant-negative proteins or complete loss of function. All IKZF1 mutations are associated with a poor prognosis. Here we review the current genetic, clinical and mechanistic evidence for the role of Ikaros as a tumor suppressor in B-ALL.
PMCID: PMC3555193  PMID: 23358883
B cell leukemia; Ikaros; tumor suppressor

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