scholarly journals Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche

2021 ◽  
Vol 9 ◽  
Author(s):  
Nitesh D. Sharma ◽  
Esra’a Keewan ◽  
Ksenia Matlawska-Wasowska
Keyword(s):  
Cell Adhesion ◽  
Acute Leukemia ◽  
Poor Prognosis ◽  
Significant Risk ◽  
Leukemic Cell ◽  
Metabolic Reprogramming ◽  
Leukemic Cells ◽  
The Central Nervous System

Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can metabolically adapt and survive in the microenvironment of the CNS. The supporting role of the CNS microenvironment in leukemia progression and dissemination has not received sufficient attention. Understanding the mechanism by which leukemic cells survive in the nutrient-poor and oxygen-deprived CNS microenvironment will lead to the development of more specific and less toxic therapies. Here, we review the current literature regarding the roles of metabolic reprogramming in leukemic cell adhesion and survival in the CNS.

scholarly journals Circulating Histone Is Elevated in Acute Leukemia and Protects Leukemic Cell Death through Enhancement of Leukemic Cell Adhesion to Endothelium

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4914-4914
Author(s):  
Hyunkyung Kim
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Cell Adhesion ◽  
Acute Leukemia ◽  
Adhesion Molecule ◽  
Neutrophil Elastase ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Endothelial Adhesion Molecule ◽  
Dna Complex

Background: Leukocytes release nuclear contents into extracellular milieu called by extracellular traps (ET) when they are stimulated by reactive oxygen species (ROS). The nuclear contents mainly compose of histone-DNA complex and neutrophil elastase. This study investigated whether the leukemic cells could release ET and the released histone could induce endothelial activation, finally resulting in leukemic progression. Methods: The circulating ET biomarkers (histone-DNA complex, cell free DNA, neutrophil elastase) were measured in 80 patients with hematologic diseases and 40 healthy controls by ELISA. ET formation and ROS level were investigated during leukemic cell proliferation in vitro. Histone-induced endothelial adhesion molecule expression and survival were measured by flow cytometry. Results: Acute leukemia showed high ET biomarkers, which correlated with peripheral blast count. Leukemic cells produced high ROS and release extracellular histone, which was significantly blocked by antioxidants. Histone significantly induced 3 endothelial adhesion molecules expression, promoting leukemic cell adhesion to endothelial cells, which was inhibited by histone inhibitors (heparin, polysialic acid, activated protein C), 3 neutralizing antibodies against adhesion molecules, and Toll like receptor(TLR)9 antagonist. When the leukemic cell co-cultured with endothelial cells, the adherent leukemic cells showed better survival than the non-adherent, demonstrating that histone-treated endothelial cells protected leukemic cells from both spontaneous and chemotherapy-induced death. Conclusion: Our data for the first time supports that extracellular histone could be released from leukemic cells through ROS dependent mechanism. The released histone could promote leukemic cell adhesion through endothelial adhesion molecule induction and finally protect from leukemic cell death. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Persistence of Extramedullary Leukemic Infiltrates during Bone Marrow Remission of Acute Leukemia

Blood ◽  
1965 ◽  
Vol 26 (2) ◽  
pp. 133-141 ◽  
Author(s):  
BOYD A. NIES ◽  
GERALD P. BODEY ◽  
LOUIS B. THOMAS ◽  
GEORGE BRECHER ◽  
EMIL J. FREIREICH
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Leukemia ◽  
Lymph Nodes ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Common Site ◽  
The Central Nervous System

Abstract Leukemic cell infiltrates were found at autopsy in the tissues of 10 of 15 patients with acute leukemia dying during "complete bone marrow remission." The kidney was the most common site of leukemic cell infiltrates followed by the liver, testes, bowel, lung, central nervous system, and lymph nodes. These findings indicate that leukemic cells are not completely eradicated by current chemotherapy even in patients in whom no leukemic cells can be identified in the bone marrow. The distribution of residual leukemic cells demonstrates that the central nervous system is not the only reservoir of leukemic cells in patients during bone marrow remission.

Covid-19 In Man: A Very Dangerous Affair.

2021 ◽  
Vol 21 ◽  
Author(s):  
Giuseppe Lisco ◽  
Vito A. Giagulli ◽  
Giovanni De Pergola ◽  
Anna De Tullio ◽  
Edoardo Guastamacchia ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Metabolic Diseases ◽  
Systemic Disease ◽  
Public Health Issue ◽  
Immune System Dysfunction ◽  
Data Support ◽  
Systemic Spread ◽  
The Impact

Background: The novel pandemic of Coronavirus disease 2019 (COVID-19) has becoming a public health issue since March 2020 considering that more than 30 million people were found to be infected worldwide. Particularly, recent evidences suggested that men may be considered as at higher risk of poor prognosis or death once the infection occurred and concerns surfaced in regard of the risk of a possible testicular injury due to SARS-CoV-2 infection. Results: Several data support the existence of a bivalent role of testosterone (T) in driving poor prognosis in patients with COVID-19. On one hand, this is attributable to the fact that T may facilitate SARS-CoV-2 entry in human cells by means of an enhanced expression of transmembrane serine-protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2). At the same time, younger man with normal testicular function compared to women of similar age are prone to develop a blunted immune response against SARS-CoV-2, being exposed to less viral clearance and more viral shedding and systemic spread of the disease. Conversely, low levels of serum T observed in hypogonadal men predispose them to a greater background systemic inflammation, cardiovascular and metabolic diseases, and immune system dysfunction, hence driving harmful consequences once SARS-CoV-2 infection occurred. Finally, SARS-CoV-2, as a systemic disease, may also affect testicles with possible concerns for current and future testicular efficiency. Preliminary data suggested that SARS-CoV-2 genome is not normally found in gonads and gametes, therefore sex transmission could be excluded as a possible way to spread the COVID-19. Conclusion: Most data support a role of T as a bivalent risk factor for poor prognosis (high/normal in younger; lower in elderly) in COVID-19. However, the impact of medical treatment aimed to modify T homeostasis for improving the prognosis of affected patients is unknown in this clinical setting. In addition, testicular damage may be a harmful consequence of the infection even in case it occurred asymptomatically but no long-term evidences are currently available to confirm and quantify this phenomenon. Different authors excluded the presence of SARS-CoV-2 in sperm and oocytes, thus limiting worries about both a potential sexual and gamete-to-embryos transmission of COVID-19. Despite these evidence, long-term and well-designed studies are needed to clarify these issues.

Neurotrophins and Proneurotrophins: Focus on Synaptic Activity and Plasticity in the Brain

2017 ◽  
Vol 23 (6) ◽  
pp. 587-604 ◽  
Author(s):  
Julien Gibon ◽  
Philip A. Barker
Keyword(s):  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Cellular Processes ◽  
Term Potentiation ◽  
Neurotrophin 3 ◽  
New Findings ◽  
The Central Nervous System ◽  
The Brain

Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.

scholarly journals Etiology of differentiated carcinoma of the thyroid current apprehension

2003 ◽  
Vol 50 (3) ◽  
pp. 51-55
Author(s):  
Ruben Han
Keyword(s):  
Animal Experiments ◽  
Growth Control ◽  
Significant Risk ◽  
Ionising Radiation ◽  
Sodium Iodide Symporter ◽  
Chemical Agents ◽  
Tsh Secretion ◽  
Genetic And Environmental Factors

It is apparent that in the last decade carcinoma of the thyroid is becoming increasingly prevalent. The multistage complex theory of thyroid carcinogenesis is based on observations made on cohort patients studies and during animal experiments over a period of last fifty years. The process of thyroid oncogenesis is conceived to be a series of events induced by genetic and environmental factors which alter follicular cells division and growth control. These factors can be considered as initiators (chemical agents and ionising radiation) and promoters (some goitrogenes and drugs). The first class of factors induce incipient tumorigenesis while the second augments TSH secretion and radically increases tumour growth. Normally silent, intracellular proto-oncogenes (of which Ret/PTC series are the most conceived ones) can become activated by chromosomal translocations, deletions or mutations and can transform normal follicular cell into a condition of uncontrolled division and growth. The most significant known cause of thyroid carcinomas in men is exposure to external or internal ionising radiation. Beside that, long-term iodine deficiency, effects of certain chemical carcinogens, drugs and goitrogenes must be considered as significant risk factors. Possible role of sodium/iodide symporter is becoming an objective of the most recent investigations.

scholarly journals The role of Neuropilin-1 in COVID-19

2021 ◽  
Vol 17 (1) ◽  
pp. e1009153
Author(s):  
Bindu S. Mayi ◽  
Jillian A. Leibowitz ◽  
Arden T. Woods ◽  
Katherine A. Ammon ◽  
Alphonse E. Liu ◽  
...  
Keyword(s):  
Immune Function ◽  
Viral Entry ◽  
Axonal Guidance ◽  
Cell Surface Receptor ◽  
Neuropilin 1 ◽  
Surface Receptor ◽  
The Central Nervous System

Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.

scholarly journals Combinations of Drugs in the Treatment of Acute Leukæmias

1965 ◽  
Vol 58 (11P2) ◽  
pp. 988-990 ◽  
Author(s):  
C Gordon Zubrod
Keyword(s):  
Acute Leukemia ◽  
Childhood Leukemia ◽  
Task Force ◽  
Leukemic Cell ◽  
The United States ◽  
Leukemic Cells ◽  
Clinical Relapse ◽  
Acute Leukemias ◽  
Human Leukemic Cells ◽  
Childhood Acute Leukemia

In the United States, the Acute Leukemia Task Force has been studying ways to achieve chemical control over the acute leukemias. It was found that L1210 mouse leukemia is an excellent predictive model for childhood acute leukemia. Examination of the kinetics of cell generation led to the conclusions that a single cell could multiply to a lethal number of cells in a relatively short time, and that therapy must destroy every cell. Extension of these hypotheses to childhood leukemia has permitted estimates of generation time of human leukemic cells; the size of the leukemic cell population at clinical relapse and the fractional destruction of cells by individual drugs. By the use of combinations of antileukemic drugs complete cell destruction has been approached in a few patients with early leukemia.

scholarly journals OX40 Expressed on Fresh Leukemic Cells From Adult T-Cell Leukemia Patients Mediates Cell Adhesion to Vascular Endothelial Cells: Implication for the Possible Involvement of OX40 in Leukemic Cell Infiltration

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2951-2958 ◽  
Author(s):  
Akihiro Imura ◽  
Toshiyuki Hori ◽  
Kazunori Imada ◽  
Shin Kawamata ◽  
Yuetsu Tanaka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Mononuclear Cells ◽  
Vascular Endothelial Cells ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia

Abstract We demonstrated previously that OX40 and its ligand, gp34, directly mediate adhesion of activated normal CD4+ T cells, as well as human T-cell leukemia virus type I (HTLV-I)–transformed T cells to vascular endothelial cells. In the present study, we examined expression of OX40 on fresh leukemic cells from patients with adult T-cell leukemia (ATL) and its possible involvement in cell adhesion. Flow cytometric analysis showed that peripheral blood mononuclear cells (PBMC) or lymph node tumor cells from 15 of 17 cases expressed significant levels of OX40 without stimulation. On the other hand, gp34 was not expressed on these cells, although its expression is also known to be associated with HTLV-I-infection. In Western blot analysis, a 50-kD protein band was detected by anti-OX40 monoclonal antibody (MoAb) in two ATL cases examined, as well as phytohemagglutinin (PHA) blasts and Hut102, an HTLV-I–infected T-cell line, but not in resting PBMC or Jurkat. Expression of OX40 mRNA was shown by reverse transcriptase-polymerase chain reaction in all ATL cases tested, PHA-blasts, and Hut102, but not in resting PBMC or Jurkat. We could not detect expression of HTLV-I viral mRNA in any of the cases tested. Cell adhesion assay was performed and in at least three cases, fresh ATL cells exhibited adhesion to human umbilical vein endothelial cells that could be considerably inhibited by either anti-OX40 MoAb or anti-gp34 MoAb. Immunohistochemical staining of skin biopsy specimens indicated that infiltrating mononuclear cells express OX40 in vivo. Taken together, these data indicate that leukemic cells from most, but not all, ATL patients constitutively express OX40, which may play a role in leukemic cell infiltration in addition to cell adhesion in vivo.

Investigating the Roles of the Yeats Domain in MLL-ENL Mediated Leukemogenesis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Hsiangyu Hu ◽  
Nirmalya Saha ◽  
Yuting Yang ◽  
Sierrah Marie Grigsby ◽  
Rolf Marschalek ◽  
...  
Keyword(s):  
Cell Growth ◽  
Acute Leukemia ◽  
Transcriptional Activation ◽  
Fusion Proteins ◽  
Conflicts Of Interest ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Fusion Partner ◽  
Wild Type

Approximately 10% of acute leukemia involves rearrangement at chromosome 11q23, giving rise to a relatively aggressive form of acute leukemia characterized by MLL1 (KMT2A) fusion proteins. Despite the identification of >100 MLL1 fusion partners, the majority are members of several similar transcriptional activation complexes including: The Super Elongation Complex (SEC), AEP and EAP (SEC used hereafter). MLL fusion-driven acute leukemia is characterized by deregulated activity of the SEC and the H3K79 methyltransferase DOT1L. This leads to altered epigenetic landscapes at and deregulated transcription of pro-leukemic MLL1-fusion target genes like HoxA9 and Meis1. Thus, targeting these transcriptional and epigenetic complexes has become an attractive therapeutic strategy for treating MLL-fusion leukemia. Eleven-Nineteen-Leukemia (ENL or MLLT1) is the third most common MLL1 fusion partner and a component of the SEC. Recently, wild type ENL was identified as an essential factor for leukemic cell growth. The ENL protein possesses a C-terminal ANC-homology domain (AHD) necessary for SEC recruitment and is essential for MLL-fusion mediated leukemogenesis. In addition, ENL contains a highly conserved N-terminal YEATS domain that functions as an epigenetic reader for acetylated H3K9, H3K18 or H3K27, which is essential for leukemic cell growth. Additionally, the ENL YEATS domain directly interacts with the Polymerase Associated Factor 1 complex (PAF1c), an epigenetic regulator protein complex essential for MLL-fusion mediated leukemogenesis. These studies highlight the importance of the YEATS domain in regulating wild type ENL function in leukemic cells. However, the importance of the YEATS domain in the context of MLL-ENL mediated leukemia remains to be elucidated. In this study, we investigate the clinical relevance and leukemic importance of the ENL YEATS domain in MLL-ENL leukemias. We first analyzed t(11;19) (MLL-ENL) patient data to determine the sites of chromosomal translocation within the ENL gene. We found that the YEATS domain (coded by exons 2 through 4) is retained in 84.1% of MLL-ENL patients (n=302). Specifically, 50.7% (n=153) of these patients possess breakpoints located 5' of the first exon of the ENL gene, while 33.4% (n=101) of the patients display breakpoints within the first intron of ENL gene. These data point towards a tendency for YEATS domain retention in MLL-ENL fusion proteins in t(11;19) patients. We next tested whether the YEATS domain was functional in MLL-ENL mouse leukemia models. Our data shows the YEATS domain is required for MLL-ENL leukemogenesis in vivo, as deletion of the YEATS domain destroys MLL-ENL leukemogenesis and increases apoptosis in cell culture. Transcriptionally, deletion of the YEATS domain decreased expression of pro-leukemic genes such as Meis1 and the anti-apoptotic gene Bclxl. To dissect the contribution of different YEATS domain functions in MLL-ENL leukemogenesis, we engineered YEATS domain mutants defective in interacting with PAF1 or acetylated H3K9/K18/K27. Disrupting the YEATS-PAF1 or YEATS-H3Kac interaction decreased MLL-ENL mediated colony formation exvivo and significantly increased leukemia latency in vivo. The MLL-ENL YEATS domain mutants will be used in future studies to determine how the YEATS domain affects 1) MLL-ENL fusion localization, 2) key protein complexes localization (i.e. SEC and PAF1c) and 3) the epigenetic landscapes (i.e. H3K79me2/3 and H3K4me3) at pro-leukemic targets. To further interrogate the YEATS-PAF1 interaction in MLL-ENL mediated leukemia, we identified the minimal region of the PAF1 protein required for the YEATS-PAF1 interaction. This PAF1 protein fragment will be used to biochemically characterize the structure of the PAF1-YEATS interaction, which might aid in therapeutically targeting specific YEATS interactions in MLL-ENL leukemia. Our results demonstrate for the first time, to our knowledge, an essential role for the YEATS domain in MLL-ENL mediated leukemogenesis. Additionally, our genetic studies elucidate the importance of the YEATS domain interaction with either the PAF1c or H3Kac in MLL-ENL leukemias. Taken together, our study establishes a rationale for exploring the effectiveness of small molecule development aimed at disrupting either the YEATS-H3Kac or the YEATS-PAF1 interaction as a therapeutic intervention for treating MLL-ENL leukemia patients. Disclosures No relevant conflicts of interest to declare.

A Critical Role of Blockade of Cell Differentiation in BCR-ABL-Induced B-Cell Acute Lymphoblastic Leukemia (B-ALL): Basis for Superb Therapeutic Effect on B-ALL in Mice by Promotion of Pro-B Leukemic Cell Differentiation and Treatment with Imatinib.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 844-844
Author(s):  
Yiguo Hu ◽  
Linghong Kong ◽  
Kevin Staples ◽  
Kevin Mills ◽  
John G. Monroe ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
B Cell Differentiation ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The BCR-ABL oncogene induces human Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) that advances to acute phase of CML called blast crisis. In this acute phase, CML patients can develop either B-ALL or acute myeloid leukemia. In B-ALL, differentiation of leukemic cells are blocked at pro-/pre-B stage, and the underlying mechanism is unknown. We hypothesize that this blockade of B-cell differentiation may be important for the development of B-ALL induced by BCR-ABL, and if so, promotion of B-leukemic cell differentiation would create a novel therapeutic strategy for B-ALL. To test this hypothesis, we first compared the percentages of IgM+ B-leukemic cells in BALB/c and C57BL/6 (B6) mice with BCR-ABL-induced B-ALL, because we have previously found that B-ALL develops more quickly in BALB/c mice than in B6 mice (Li et al, J. Exp. Med.189:1399–1412, 1999). We expressed BCR-ABL in bone marrow (BM) using retroviral transduction and transplantation in these two different strains of inbred mice to induce B-ALL. There were significantly more peripheral blood B220+ B cells in BALB/c B-ALL mice than those in B6 mice, correlating to faster B-ALL in BALB/c mice than in B6 mice. Among these B220+ cells, IgM+ cells were much less in BALB/c mice than in B6 mice. We also compared rearrangement of the B cell antigen receptor (BCR) heavy chains (m chains) between BALB/c and B6 backgrounds using BCR-ABL-expressing pro-B cell lines isolated from the B-ALL mice. Normal m chains rearrangement was found in B6 leukemic cells, but not in BALB/c leukemic cells. These results indicate that more differentiated B-leukemic cells are associated with less aggressive disease. To further demonstrate the role of blockade of B-cell differentiation in B-ALL development, we induced B-leukemic cell differentiation by co-expression of BCR-ABL and intact immunoregulatory tyrosine activation motifs (ITAM) contained in immunoglobulin (Ig)_/Igß complexes in BM cells of B-ALL mice, comparing to expression of BCR-ABL alone. We treated these mice with imatinib (orally, 100 mg/kg, twice a day). The treated mice with B-ALL induced by co-expression of BCR-ABL and ITAM lived three-week longer than those with B-ALL induced by BCR-ABL only, with some mice in long-term remission. Prolonged survival was associated with 50% increased B220+/IgM+ B-leukemic cells in peripheral blood of the mice. Taken together, our results demonstrate that blockade of B-cell differentiation is critical for the development of B-ALL induced by BCR-ABL, and provide a rationale for combination therapy of B-ALL with imatinib and induction of leukemic cell differentiation.

Sign in / Sign up

Export Citation Format

Share Document