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acute leukemia pathophysiology

Hubo Li, Brenton G Mar, Huadi Zhang, Rishi V Puram, Francisca Vazquez, Barbara A Weir, William C Hahn, Benjamin Ebert, David Pellman
Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale shRNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein...
October 18, 2016: Blood
Michael Medinger, Claudia Lengerke, Jakob Passweg
Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence is increasing as the population ages. Cytogenetic anomalies and mutation testing remain important prognostic tools for tailoring treatment after induction therapy. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, as well as the rapid development of new drugs, standard treatment options have not experienced major changes during the past three decades...
2016: Leukemia Research Reports
Motoshi Ichikawa
Myelodysplastic syndromes (MDS) are characterized by clonal proliferation of hematopoietic stem/progenitor cells and their apoptosis, and show a propensity to progress to acute myelogenous leukemia (AML). Although MDS are recognized as neoplastic diseases caused by genomic aberrations of hematopoietic cells, the details of the genetic abnormalities underlying disease development have not as yet been fully elucidated due to difficulties in analyzing chromosomal abnormalities. Recent advances in comprehensive analyses of disease genomes including whole-genome sequencing technologies have revealed the genomic abnormalities in MDS...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Karmen Stankov, Sunčica Stankov, Jasmina Katanić
BACKGROUND: Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders of hematopoietic system, characterized by genetic, epigenetic or microenvironmental alterations of aging hematopoietic stem cells. Pathophysiology of MDS comprises the suppression of normal hematopoiesis and reduced myeloid progenitor cells differentiation, with the main consequence of peripheral cytopenias and increased risk to evolution in acute myeloid leukemia (AML). METHOD: This review summarizes the evolving understanding of the role of genetic and epigenetic alterations involved in pathogenesis and current and future strategies for therapeutic targeting in myelodysplastic syndromes...
October 3, 2016: Current Pharmaceutical Design
Jeanette Prada-Arismendy, Johanna C Arroyave, Sarah Röthlisberger
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The pathophysiology of this disease is just beginning to be understood at the cellular and molecular level, and currently cytogenetic markers are the most important for risk stratification and treatment of AML patients. However, with the advent of new technologies, the detection of other molecular markers such as point mutations and characterization of epigenetic and proteomic profiles, have begun to play an important role in how the disease is approached...
September 2, 2016: Blood Reviews
Isabel Gonçalves Silva, Laura Rüegg, Bernhard F Gibbs, Marco Bardelli, Alexander Fruehwirth, Luca Varani, Steffen M Berger, Elizaveta Fasler-Kan, Vadim V Sumbayev
The immune receptor Tim-3 is often highly expressed in human acute myeloid leukemia (AML) cells where it acts as a growth factor and inflammatory receptor. Recently, it has been demonstrated that Tim-3 forms an autocrine loop with its natural ligand galectin-9 in human AML cells. However, the pathophysiological functions of Tim-3 in human AML cells remain unclear. Here, we report for the first time that Tim-3 is required for galectin-9 secretion in human AML cells. However, this effect is cell-type specific and was found so far to be applicable only to myeloid (and not, for example, lymphoid) leukemia cells...
July 2016: Oncoimmunology
Gunnar Juliusson, Rachael Hough
Leukemias are a group of life threatening malignant disorders of the blood and bone marrow. In the adolescent and young adult (AYA) population, the acute leukemias are most prevalent, with chronic myeloid leukemia being infrequently seen. Factors associated with more aggressive disease biology tend to increase in frequency with increasing age, whilst tolerability of treatment strategies decreases. There are also challenges regarding the effective delivery of therapy specific to the AYA group, consequences on the unique psychosocial needs of this age group, including compliance...
2016: Progress in Tumor Research
Michael Medinger, Claudia Lengerke, Jakob Passweg
Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence increases with age. Cytogenetics and mutation testing remain important prognostic tools for treatment after induction therapy. The post-induction treatment is dependent on risk stratification. Despite rapid advances in determination of gene mutations involved in the pathophysiology and biology of AML, and the rapid development of new drugs, treatment improvements changed slowly over the past 30 years, with the majority of patients eventually experiencing relapse and dying of their disease...
September 2016: Cancer Genomics & Proteomics
Sowmya Nanjappa, Daniel K Jeong, Manjunath Muddaraju, Katherine Jeong, Ebone D Hill, John N Greene
Diffuse alveolar hemorrhage is a potentially fatal pulmonary disease syndrome that affects individuals with hematological and nonhematological malignancies. The range of inciting factors is wide for this syndrome and includes thrombocytopenia, underlying infection, coagulopathy, and the frequent use of anticoagulants, given the high incidence of venous thrombosis in this population. Dyspnea, fever, and cough are commonly presenting symptoms. However, clinical manifestations can be variable. Obvious bleeding (hemoptysis) is not always present and can pose a potential diagnostic challenge...
July 2016: Cancer Control: Journal of the Moffitt Cancer Center
Craig E Eckfeldt, Emily J Pomeroy, Robin D W Lee, Katherine S Hazen, Lindsey A Lee, Branden S Moriarity, David A Largaespada
Mutations that activate RAS proto-oncogenes and their effectors are common in acute myeloid leukemia (AML); however, efforts to therapeutically target Ras or its effectors have been unsuccessful, and have been hampered by an incomplete understanding of which effectors are required for AML proliferation and survival. We investigated the role of Ras effector pathways in AML using murine and human AML models. Whereas genetic disruption of NRAS(V12) expression in an NRAS(V12) and Mll-AF9-driven murine AML induced apoptosis of leukemic cells, inhibition of phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) signaling did not reproduce this effect...
August 20, 2016: Oncotarget
Oscar A Marcos-Contreras, Sara Martinez de Lizarrondo, Isabelle Bardou, Cyrille Orset, Mathilde Pruvost, Antoine Anfray, Yvann Frigout, Yannick Hommet, Laurent Lebouvier, Joan Montaner, Denis Vivien, Maxime Gauberti
Hyperfibrinolysis is a systemic condition occurring in various clinical disorders such as trauma, liver cirrhosis or leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our present aim was to develop an experimental model of hyperfibrinolysis and to study its effects on the homeostasis of the blood brain barrier (BBB). We induced a sustained hyperfibrinolytic state in mice by hydrodynamic transfection of a plasmid encoding for tissue-type plasminogen activator (tPA)...
August 16, 2016: Blood
Fortunato Morabito, Maria Teresa Voso, Stefan Hohaus, Massimo Gentile, Ernesto Vigna, Anna Grazia Recchia, Lorenzo Iovino, Edoardo Benedetti, Francesco Lo-Coco, Sara Galimberti
INTRODUCTION: Therapeutic strategies in patients with acute myeloid leukemia (AML) have not changed significantly over the last decades. Appropriate strategies are ultimately driven by the assessment of patients' fitness to define suitability for intensive induction chemotherapy, which produces high initial remission rates but, increased likelihood of relapse. Old/unfit AML patients still represent an urgent and unmet therapeutic need. Epigenetic deregulation represents a strategic characteristic of AML pathophysiology whereby aberrant gene transcription provides an advantage to leukemic cell survival...
September 2016: Expert Opinion on Investigational Drugs
Vuk Palibrk, Rajikala Suganthan, Katja Scheffler, Wei Wang, Magnar Bjørås, Stig Ove Bøe
Regulation of innate immune responses and activation of tissue regenerative processes are key elements in the pathophysiology of brain injuries. The promyelocytic leukemia (PML) gene was originally identified on a breakpoint of chromosomal translocation t(15;17) associated with acute PML. We have studied the role of PML protein during acute and regenerative phases after hypoxia-ischemia (HI) in brains of neonatal mice. We found that PML prevents tissue loss and apoptotic cell death selectively in subcortical regions of the brain at early stages after damage...
2016: Cell Death & Disease
Joanne M Kingsbury, Nachiketha Shamaprasad, R Blake Billmyre, Joseph Heitman, Maria E Cardenas
A major advance in understanding the progression and prognostic outcome of certain cancers, such as low-grade gliomas, acute myeloid leukemia, and chondrosarcomas, has been the identification of early-occurring mutations in the NADP(+)-dependent isocitrate dehydrogenase genes IDH1 and IDH2 These mutations result in the production of the onco-metabolite D-2-hydroxyglutarate (2HG), thought to contribute to disease progression. To better understand the mechanisms of 2HG pathophysiology, we introduced the analogous glioma-associated mutations into the NADP(+) isocitrate dehydrogenase genes (IDP1, IDP2, IDP3) in Saccharomyces cerevisiae Intriguingly, expression of the mitochondrial IDP1(R148H) mutant allele results in high levels of 2HG production as well as extensive mtDNA loss and respiration defects...
July 17, 2016: Human Molecular Genetics
Katerina Cermakova, Caroline Weydert, Frauke Christ, Jan De Rijck, Zeger Debyser
Protein-protein interactions are involved in most if not all pathogenic and pathophysiological processes and represent attractive therapeutic targets. Extensive biological and clinical research efforts have led to the identification and validation of several cellular hubs that are crucially involved in disease pathogenesis. An interesting example of such a hub is the lens epithelium-derived growth factor (LEDGF/p75), a protein that tethers multiple unrelated proteins and protein complexes to the chromatin. Its chromatin-tethering ability is linked to at least two unrelated diseases-HIV infection and MLL-rearranged acute leukemia...
August 2016: Trends in Pharmacological Sciences
Elli Papaemmanuil, Moritz Gerstung, Lars Bullinger, Verena I Gaidzik, Peter Paschka, Nicola D Roberts, Nicola E Potter, Michael Heuser, Felicitas Thol, Niccolo Bolli, Gunes Gundem, Peter Van Loo, Inigo Martincorena, Peter Ganly, Laura Mudie, Stuart McLaren, Sarah O'Meara, Keiran Raine, David R Jones, Jon W Teague, Adam P Butler, Mel F Greaves, Arnold Ganser, Konstanze Döhner, Richard F Schlenk, Hartmut Döhner, Peter J Campbell
BACKGROUND: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODS: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes...
June 9, 2016: New England Journal of Medicine
Laixi Bi, Junqing Wu, Aifang Ye, Jianbo Wu, Kang Yu, Shenghui Zhang, Yixiang Han
BACKGROUND: Immune regulation is crucial for the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL). It has been reported that Th17 cells as a newly identified subset of CD4(+) T cells are involved in the pathogenesis of several hematological disorders. However, the role of Th17 cells in the pathophysiology of B-ALL is still unclear. METHODS: The frequencies of T cells were determined by flow cytometry in the peripheral blood and bone marrow of 44 newly diagnosed B-ALL patients and 25 age-matched healthy donors...
2016: Journal of Translational Medicine
Mohammad Faizan Zahid, Mrinal M Patnaik, Naseema Gangat, Shahrukh K Hashmi, David A Rizzieri
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor-alpha, interferon-gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1)...
October 2016: European Journal of Haematology
Christina T Rieger, Michael Fiegl
Reduced oxygen partial pressure (pO2) has been recognized as being relevant in hematopoiesis and the pathophysiology of malignant diseases. Although hypoxic (meaning insufficient supply of oxygen) and anoxic areas are present and of pathophysiologic importance (by hypoxia-induced pathways such as HiF1α) in solid tumors, this may not be true for (malignant) hematologic cells. Hematopoiesis occurs in the stem cell niche, which is characterized, among other things, by extremely low pO2. However, in contrast to solid tumors, in this context, the low pO2 is physiological and this feature, among others, is shared by the malignant stem cell niche harboring leukemia-initiating cells...
July 2016: Experimental Hematology
Kamel Laribi, Nathalie Denizon, Anne Besançon, Jonathan Farhi, Pierre Lemaire, Jeremy Sandrini, Catherine Truong, Habib Ghnaya, Alix Baugier de Materre
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. It is grouped with acute myeloid leukemia-related precursor neoplasms in the 2008 World Health Organization classification. Most patients with BPDCN have skin lesions at diagnosis and subsequent or simultaneous involvement of the bone marrow, peripheral blood, and lymph nodes. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplantation may improve survival...
August 2016: Biology of Blood and Marrow Transplantation
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