Antiapoptotic proteins as prognostic markers and resistance mechanisms in Acute Myeloid Leukemia PDF Download
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Author: Ingo Tamm
Publisher:
ISBN:
Category :
Languages : de
Pages : 256
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Author: Ingo Tamm
Publisher:
ISBN:
Category :
Languages : de
Pages : 256
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Author: Ingrid Jakobsen
Publisher: Linköping University Electronic Press
ISBN: 9176851958
Category :
Languages : en
Pages : 76
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Book Description
The standard treatment of acute myeloid leukemia (AML) consists of induction chemotherapy, most commonly daunorubicin together with the nucleoside analogue cytarabine (Ara-C), followed by consolidation chemotherapy and in selected cases allogenic stem cell transplantation (allo-SCT). Despite a high initial response rate, a considerable proportion of all AML cases eventually suffer from relapse and the five-year overall survival rate in patients >60 years is only around 15%. Based on cytogenetic analysis, patients are divided into low risk, intermediate risk, and high-risk groups. While low risk patients have a high chance of reaching and remaining in remission after standard induction therapy, high-risk patients are likely to suffer from relapse and should be scheduled for allo-SCT when first complete remission is reached. The intermediate risk group consists of normal karyotype (NK) patients and those with karyotypes of uncertain clinical relevance, but the outcomes are heterogeneous. In NKAML patients, risk classification has improved with the addition of molecular markers including FLT3 internal tandem duplications (ITD) and mutations of NPM1 and CEBPA. Despite this development, there is a group of patients lacking reliable prognostic markers and in some cases the outcomes predicted do not match the outcomes observed, highlighting the need for additional markers. ABCB1 encodes a transporter protein responsible for the extrusion of cytotoxic compounds, including daunorubicin, over the cell membrane, and is a known resistance mechanism. Ara-C is subject to both activating and inactivating metabolic enzymes including DCK (activating), CDA and cN-II (inactivating). ABCB1, DCK, CDA and cN-II are all polymorphic, and SNPs affecting enzyme function and/or activity have potential as prognostic markers. In addition, recurrent IDH1/2 mutations lead to the expression of an enzyme with neomorphic activity associated with epigenetic alterations and disturbed differentiation. Mutations as well as a SNP in codon 105 of IDH1 have prognostic implications in AML, although the effects of different IDH mutations have been unclear. The aim of this thesis was to investigate SNPs in ABCB1 and genes associated with Ara-C metabolism, mutations in IDH1/2 and the IDH1 SNP, and their associations with treatment response and survival in AML. We show that the 1236C>T and 2677G>T SNPs in ABCB1 influence in vitro sensitivity towards AML drugs, with corresponding effects on NK-AML patient survival. These survival differences were seen mainly in patients lacking FLT3-ITD, further adding to the risk stratification. In contrast, the CDA SNPs 79A>C and -451C>T appear to influence survival mainly in FLT3-ITD positive cases. In conclusion, the above-mentioned SNPs have the potential to add important information to risk classifications especially in NK-AML patients with the ambiguous FLT3-ITD-/NPM1- or FLT3-ITD+/NPM1+ genotypes. In addition, we have shown that IDH2 R140 mutation is associated with impaired survival in AML, and that the IDH1 codon 105 SNP appears to confer a worse outcome in a subset of intermediate risk patients without FLT3-ITD. With the introduction of next generation sequencing into clinical diagnostics, IDH mutations may not only provide prognostic information but also guide the selection of patients for new drugs targeting the variant enzyme. Our results indicate that in addition to leukemia-specific mutations, constitutional SNPs may prove useful for further individualizing care-taking and should be considered when implementing these new techniques.
Author: Sadie Steffens
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Acute myeloid leukemia (AML) is a malignant disease of the myeloid line of blood cells and is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Cytarabine and other currently available treatments for acute myeloid leukemia are highly toxic and insufficient, as more than half of all AML patients develop resistance to chemotherapeutic agents. Since AML often affects older people who are less tolerant of chemotherapy, there is need for novel, targeted, less toxic drugs in order to improve survival for this disease. Casein Kinase II (CK2) is a pro-oncogenic serine/threonine kinase that is essential for cellular proliferation. Overexpression or increased CK2 activity is associated with various types of human malignancies. In hematopoietic cells, increased CK2 expression is associated with malignant transformation and development of leukemia. Increased CK2 activity is associated with a poor prognosis in AML. Targeted inhibition of CK2 with a novel, specific inhibitor produced a strong anti-leukemia effect in vitro and in pre-clinical models. However, the mechanism through which CK2 inhibitors exert an anti-leukemia effect is unknown. The goal of our project is to identify the mechanism of the therapeutic activity of CK2 inhibition using CX-4945 in AML. Ikaros is a zinc finger, DNA-binding protein that is encoded by the IKZF1 gene and acts as a tumor suppressor in hematopoietic malignancies. Deletion or functional inactivation of Ikaros is associated with development of high-risk acute lymphoblastic leukemia (ALL) as well as AML. Previously published data showed that CK2 directly phosphorylates Ikaros at multiple evolutionarily-conserved sites. The CK2-mediated phosphorylation of Ikaros results in reduced DNA-binding affinity and loss of Ikaros function as a transcriptional regulator of gene expression. Inhibition of CK2 restores Ikaros function as a tumor suppressor and produces an anti-leukemia effect in ALL. Based on these data, we hypothesized that one of the mechanisms of therapeutic action of CK2 inhibitors in AML involves restoration of Ikaros function as a transcriptional regulator of genes involved in malignant transformation. Genome-wide binding studies using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) demonstrated that inhibition of CK2 via CX-4945 in U937 and primary AML cells enhances Ikaros binding affinity at the promoter regions of its target genes. We used gain-of-function and loss-of-function experiments to determine how Ikaros regulates several novel target genes involved in malignant transformation and drug resistance. Results demonstrated that Ikaros directly represses transcription of the BCL2A1 gene, which promotes leukemogenesis and has an anti-apoptotic function. We show that the ability of Ikaros to repress transcription of BCL2A1 is impaired in AML, overexpression of BCL2A1 is a negative prognostic marker, and anti-apoptotic mechanisms contribute to resistance to chemotherapy. Repression of BCL2A1 results in increased apoptosis. The ability of Ikaros to repress BCL2A1 transcription is impaired by CK2. Inhibition of CK2 via CX-4945 increases Ikaros binding at the BCL2A1 promoter, resulting in transcriptional repression of BCL2A1. Increased Ikaros binding to the BCL2A1 promoter is associated with formation of repressive chromatin that is characterized by the loss of the positive marker H3K4me2 and increase in the negative marks H3K9me3 and H3K27me3. Since BCL2A1 has an anti-apoptotic function, we tested whether CK2 inhibition increases susceptibility of AML cells to apoptosis. Results showed that CK2 inhibition increases apoptosis of AML cells and that the CK2 inhibitor CX-4945 has synergistic therapeutic effects in combination with a standard drug for AML, Doxorubicin. These data indicate a new Ikaros target gene, one mechanism for the therapeutic activity of CK2 inhibition, and a novel combination treatment for AML.Similar functional experiments were performed on four additional Ikaros target genes that were identified by ChIP-Seq (MTHFR, CDA, DLX1, and DLX2). Results demonstrated that CK2 impairs transcriptional regulation of these genes by Ikaros in AML. Treatment with CK2 inhibitor restores Ikaros-mediated regulation of these genes. Since two of the newly-identified Ikaros target genes are known to be involved in drug resistance, the therapeutic effect of the CK2 inhibitor CX-4945 has been tested in combination with additional chemotherapeutic agents, and results showed a synergistic effect of these combination treatments in AML cells.Finally, a systems biology approach was used to determine the effect of CK2 inhibition on the epigenome and transcriptome of AML cells. The analysis revealed that CK2 inhibition results in alterations in the epigenomic signature of AML cells. The prominent changes involved alteration of enhancer and super-enhancer landscapes, which were associated with transcriptional regulation of many genes that are critical for cellular proliferation.In summary, our results demonstrate that the therapeutic effect of CK2 inhibition in AML cells involves restoration of Ikaros function as a tumor suppressor and transcriptional regulator. Our results have identified novel pathways that are regulated by Ikaros as well as an epigenomic landscape that is regulated by CK2. These data led to the development of novel combination treatments for AML which showed synergy when tested on AML cells. Our results provide a mechanistic rationale for development of novel, targeted treatments for AML.
Author: Hillard M. Lazarus
Publisher: Springer Science & Business Media
ISBN: 1597454788
Category : Medical
Languages : en
Pages : 885
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Book Description
Since the original publication of Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Allogeneic hematopoietic stem cell transplantation (HSC) has undergone several fast-paced changes. In this second edition, the editors have focused on topics relevant to evolving knowledge in the field in order to better guide clinicians in decision-making and management of their patients, as well as help lead laboratory investigators in new directions emanating from clinical observations. Some of the most respected clinicians and scientists in this discipline have responded to the recent advances in the field by providing state-of-the-art discussions addressing these topics in the second edition. The text covers the scope of human genomic variation, the methods of HLA typing and interpretation of high-resolution HLA results. Comprehensive and up-to-date, Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Second Edition offers concise advice on today's best clinical practice and will be of significant benefit to all clinicians and researchers in allogeneic HSC transplantation.
Author: Wojciech Gorczyca
Publisher: CRC Press
ISBN: 9781841845548
Category : Medical
Languages : en
Pages : 332
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Book Description
Effective treatment of the tumors of the hematopoietic system now often depends on an exact prognosis for the disorder concerned, and so the hematopathologist can give vital direction to the hematologic or oncologic clinician. Prognostic Markers in Hematologic Oncology comprehensively presents the numerous predictive and prognostic parameters in the practice of oncologic haematology and underlines their clinical relevance.
Author: Claudio Ortolani
Publisher: John Wiley & Sons
ISBN: 111961130X
Category : Medical
Languages : en
Pages : 464
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Book Description
Flow Cytometry of Hematological Malignancies Flow cytometric analysis is often integral to the swift and accurate diagnosis of leukemias and lymphomas of the blood, bone marrow, and lymph nodes. However, in the fast-moving and expanding field of clinical hematology, in can be challenging to remain up to speed with the latest biological research and technological innovations. Flow Cytometry of Hematological Malignancies has been designed to provide all those working in hematological oncology with a practical, cutting-edge handbook, featuring clear and fully illustrated guidance on all aspects of cytometry’s role in diagnosis and analysis. This essential second edition includes: Explorations of more than 70 antigens Full-color illustrations throughout New descriptions of recently discovered markers WHO classifications of hematological neoplastic diseases Helpful tips for result interpretation and analysis Featuring all this and more, Flow Cytometry of Hematological Malignancies, Second Edition, is an invaluable resource for both trainee and experienced hematologists, hematopathologists, oncologists, and pathologists, as well as medical students and diagnostic lab technicians.
Author: Stuart K. Calderwood
Publisher: Springer Science & Business Media
ISBN: 1402064012
Category : Medical
Languages : en
Pages : 399
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Book Description
Heat shock proteins are emerging as important molecules in the development of cancer and as key targets in cancer therapy. These proteins enhance the growth of cancer cells and protect tumors from treatments such as drugs or surgery. However, new drugs have recently been developed particularly those targeting heat shock protein 90. As heat shock protein 90 functions to stabilize many of the oncogenes and growth promoting proteins in cancer cells, such drugs have broad specificity in many types of cancer cell and offer the possibility of evading the development of resistance through point mutation or use of compensatory pathways. Heat shock proteins have a further property that makes them tempting targets in cancer immunotherapy. These proteins have the ability to induce an inflammatory response when released in tumors and to carry tumor antigens to antigen presenting cells. They have thus become important components of anticancer vaccines. Overall, heat shock proteins are important new targets in molecular cancer therapy and can be approached in a number of contrasting approaches to therapy.
Author: Zahra Zakeri
Publisher:
ISBN:
Category : Science
Languages : en
Pages : 236
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Book Description
Contains papers from a July 1998 conference held at the Queens College Campus of the City University of New York. Papers are arranged in sections on mechanisms and general considerations, programmed (developmental) cell death, and cell death and pathological and clinical situations. Specific topics
Author: United States. Public Health Service. Office of the Surgeon General
Publisher:
ISBN:
Category : Government publications
Languages : en
Pages : 728
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Book Description
This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.
Author: Enrico Mihich
Publisher: Springer Science & Business Media
ISBN: 1461519276
Category : Medical
Languages : en
Pages : 251
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Book Description
''An exciting glance at key issues in contemporary hematopoiesis.'' -The Quarterly Review of Biology
