Development of Murine Leukemia Virus Integrase-Derived Peptides That Bind Brd4 Extra-Terminal Domain as Candidates for Suppression of Acute Myeloid Leukemia

2021 ◽  
Vol 4 (5) ◽  
pp. 1628-1638
Author(s):  
Enming Xing ◽  
Nandini Surendranathan ◽  
Xiaotian Kong ◽  
Natalie Cyberski ◽  
Jessica D. Garcia ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Murine Leukemia Virus ◽  
Myeloid Leukemia ◽  
Leukemia Virus ◽  
Terminal Domain ◽  
Murine Leukemia ◽  
Acute Myeloid

scholarly journals Mutation of All Runx (AML1/Core) Sites in the Enhancer of T-Lymphomagenic SL3-3 Murine Leukemia Virus Unmasks a Significant Potential for Myeloid Leukemia Induction and Favors Enhancer Evolution toward Induction of Other Disease Patterns

2004 ◽  
Vol 78 (23) ◽  
pp. 13216-13231 ◽  
Author(s):  
Karina Dalsgaard Sørensen ◽  
Leticia Quintanilla-Martinez ◽  
Sandra Kunder ◽  
Jörg Schmidt ◽  
Finn Skou Pedersen
Keyword(s):  
T Cell ◽  
Murine Leukemia Virus ◽  
Myeloid Leukemia ◽  
Leukemia Virus ◽  
Color Flow ◽  
Potent Inducer ◽  
Induced Tumors ◽  
Myeloid Leukemias ◽  
T Lymphomas ◽  
Murine Leukemia

ABSTRACT SL3-3 murine leukemia virus is a potent inducer of T-lymphomas in mice. Using inbred NMRI mice, it was previously reported that a mutant of SL3-3 with all enhancer Runx (AML1/core) sites disrupted by 3-bp mutations (SL3-3dm) induces predominantly non-T-cell tumors with severely extended latency (S. Ethelberg, J. Lovmand, J. Schmidt, A. Luz, and F. S. Pedersen, J. Virol. 71:7273-7280, 1997). By use of three-color flow cytometry and molecular and histopathological analyses, we have now performed a detailed phenotypic characterization of SL3-3- and SL3-3dm-induced tumors in this mouse strain. All wild-type induced tumors had clonal T-cell receptor β rearrangements, and the vast majority were CD3+ CD4+ CD8− T-lymphomas. Such a consistent phenotypic pattern is unusual for murine leukemia virus-induced T-lymphomas. The mutant virus induced malignancies of four distinct hematopoietic lineages: myeloid, T lymphoid, B lymphoid, and erythroid. The most common disease was myeloid leukemia with maturation. Thus, mutation of all Runx motifs in the enhancer of SL3-3 severely impedes viral T-lymphomagenicity and thereby discloses a considerable and formerly unappreciated potential of this virus for myeloid leukemia induction. Proviral enhancers with complex structural alterations (deletions, insertions, and/or duplications) were found in most SL3-3dm-induced T-lymphoid tumors and immature myeloid leukemias but not in any cases of myeloid leukemia with maturation, mature B-lymphoma, or erythroleukemia. Altogether, our results indicate that the SL3-3dm enhancer in itself promotes induction of myeloid leukemia with maturation but that structural changes may arise in vivo and redirect viral disease specificity to induction of T-lymphoid or immature myeloid leukemias, which typically develop with moderately shorter latencies.

scholarly journals Novel Insights into the Pathogenesis of the Graffi Murine Leukemia Retrovirus

2006 ◽  
Vol 80 (8) ◽  
pp. 4026-4037 ◽  
Author(s):  
Véronique Voisin ◽  
Corinne Barat ◽  
Trang Hoang ◽  
Eric Rassart
Keyword(s):  
B Cell ◽  
Murine Leukemia Virus ◽  
Myeloid Leukemia ◽  
Morphological Analysis ◽  
Leukemia Virus ◽  
Blood Smears ◽  
Myeloid Leukemias ◽  
Disease Specificity ◽  
Different Strains ◽  
Murine Leukemia

ABSTRACT The Graffi murine leukemia virus (MuLV) was isolated in 1954 by Arnold Graffi, who characterized it as a myeloid leukemia-inducing retrovirus. He and his team, however, soon observed the intriguing phenomenon of hematological diversification, which corresponded to a decrease of myeloid leukemias and an increase of other types of leukemias. Recently, we derived two different molecular clones corresponding to ecotropic nondefective genomes that were named GV-1.2 and GV-1.4. The induced leukemias were classified as myeloid based on morphological analysis of blood smears. In this study, we further characterized the two variants of the Graffi murine retrovirus, GV-1.2 and GV-1.4, in three different strains of mice. We show that the Graffi MuLV is a multipotent retrovirus capable of inducing both lymphoid (T- and B-cell) and nonlymphoid (myeloid, erythroid, megakaryocytic) leukemia. Many of these are very complex with concomitant expression of different hematopoietic lineages. Interestingly, a high percentage of megakaryocytic leukemias, a type of leukemia rarely observed with MuLVs, arise in the FVB/n strain of mice. The genetic backgrounds of the different strains of mice influence greatly the results. Furthermore, the enhancer region, different for GV-1.2 and GV-1.4, plays a pivotal role in the disease specificity: GV-1.2 induces more lymphoid leukemias, and GV-1.4 induces more nonlymphoid ones.

scholarly journals Mutational Analysis of the N-Terminal Domain of Moloney Murine Leukemia Virus Capsid Protein

2007 ◽  
Vol 81 (22) ◽  
pp. 12337-12347 ◽  
Author(s):  
Marcy R. Auerbach ◽  
Kristy R. Brown ◽  
Ila R. Singh
Keyword(s):  
Murine Leukemia Virus ◽  
Mutational Analysis ◽  
Leukemia Virus ◽  
Host Protein ◽  
Moloney Murine Leukemia Virus ◽  
Structural Defects ◽  
Retroviral Infection ◽  
Functional Region ◽  
Terminal Domain ◽  
Murine Leukemia

ABSTRACT Retroviral capsid (CA) proteins contain a structurally conserved N-terminal domain (NTD) consisting of a β-hairpin and six to seven α-helices. To examine the role of this domain in Moloney murine leukemia virus (MoMLV) replication, we analyzed 18 insertional mutations in this region. All mutants were noninfectious. Based on the results of this analysis and our previous studies on additional mutations in this domain, we were able to divide the NTD of MoMLV CA into three functional regions. The first functional region included the region near the N terminus that forms the β-hairpin and was shown to control normal maturation of virions. The second region included the helix 4/5 loop and was essential for the formation of spherical cores. The third region encompassed most of the NTD except for the above loop. Mutants of this region assembled imperfect cores, as seen by detailed electron microscopy analyses, yet the resulting particles were efficiently released from cells. The mutants were defective at a stage immediately following entry of the core into cells. Despite possessing functional reverse transcriptase machinery, these mutant virions did not initiate reverse transcription in cells. This block could be due to structural defects in the assembling core or failure of an essential host protein to interact with the mutant CA protein, both of which may prevent correct disassembly upon entry of the virus into cells. Future studies are needed to understand the mechanism of these blocks and to target these regions pharmacologically to inhibit retroviral infection at additional stages.

scholarly journals Large-Scale Identification of Disease Genes Involved in Acute Myeloid Leukemia

2004 ◽  
Vol 78 (4) ◽  
pp. 1971-1980 ◽  
Author(s):  
Stefan J. Erkeland ◽  
Marijke Valkhof ◽  
Claudia Heijmans-Antonissen ◽  
Antoinette van Hoven-Beijen ◽  
Ruud Delwel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Leukemia Virus ◽  
Point Mutations ◽  
Insertion Mutagenesis ◽  
Disease Genes ◽  
Integration Sites ◽  
Virus Integration ◽  
Acute Myeloid

ABSTRACT Acute myeloid leukemia (AML) is a heterogeneous group of diseases in which chromosomal aberrations, small insertions or deletions, or point mutations in certain genes have profound consequences for prognosis. However, the majority of AML patients present without currently known genetic defects. Retroviral insertion mutagenesis in mice has become a powerful tool for identifying new disease genes involved in the pathogenesis of leukemia and lymphoma. Here we have used the Graffi-1.4 strain of murine leukemia virus, which causes predominantly AML, in a screen to identify novel genes involved in the pathogenesis of this disease. We report 79 candidate disease genes in common integration sites (CISs) and 15 genes whose family members previously were found to be affected in other studies. The majority of the identified sequences (60%) were not found in lymphomas and monocytic leukemias in previous screens, suggesting a specific involvement in AML. Although most of the virus integrations occurred in or near the 5′ or 3′ ends of the genes, suggesting deregulation of gene expression as a consequence of virus integration, 18 CISs were located exclusively within the genes, conceivably causing gene disruption.

scholarly journals Anti-CD71 antibody immunohistochemistry in the diagnosis of acute myeloid leukemia, subtype acute erythroid leukemia with erythroid dominance (AML M6-Er), in a retrovirus-negative cat

2020 ◽  
Vol 33 (1) ◽  
pp. 87-94
Author(s):  
Satoshi Suzuki ◽  
Naotaka Ogino ◽  
Ikki Mitsui ◽  
Hiroyuki Ito ◽  
Takuro Kariya
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Virus ◽  
Peripheral Blood Smear ◽  
Feline Leukemia Virus ◽  
Erythroid Hyperplasia ◽  
Pathologic Features ◽  
Erythroid Precursors ◽  
Acute Myeloid

CD71 is an immunohistochemical marker used in diagnosing acute myeloid leukemia (AML) M6-Er in humans; however, to our knowledge, it has not been reportedly used for immunohistochemistry in veterinary medicine. We evaluated the pathologic features of AML M6-Er in a retrovirus-negative cat and used CD71 to support the diagnosis. A 4-y-old spayed female Scottish Fold cat was presented with lethargy, anorexia, and fever. Whole-blood PCR assay results for pro feline leukemia virus/pro feline immunodeficiency virus and feline vector-borne diseases were negative. Early erythroid precursors were observed in the peripheral blood smear. Fine-needle aspiration of the enlarged spleen and splenic lymph node showed many early erythroid precursors. Bone marrow aspirate smears revealed erythroid hyperplasia with 68.4% erythroid lineage and 3.6% rubriblasts. Dysplastic cells infiltrated other organs. The patient was diagnosed with myelodysplastic syndrome, progressing to the early phase of AML M6-Er. The patient died on day 121 despite multidrug treatments. Postmortem examination revealed neoplastic erythroblasts infiltrating the bone marrow and other organs. Neoplastic cells were immunopositive for CD71 but immunonegative for CD3, CD20, granzyme B, von Willebrand factor, CD61, myeloperoxidase, and Iba-1. Although further studies are necessary for the application of CD71, our results supported the morphologic diagnosis of AML M6-Er.

scholarly journals Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 531 ◽  
Author(s):  
Lisa Lirussi ◽  
Giulia Antoniali ◽  
Pasqualina Liana Scognamiglio ◽  
Daniela Marasco ◽  
Emiliano Dalla ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Acceptor Site ◽  
Dna Damages ◽  
Multifunctional Protein ◽  
Terminal Domain ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

Apurinic/apyrimidinic endonuclease 1 (APE1), the main mammalian AP-endonuclease for the resolution of DNA damages through the base excision repair (BER) pathway, acts as a multifunctional protein in different key cellular processes. The signals to ensure temporo-spatial regulation of APE1 towards a specific function are still a matter of debate. Several studies have suggested that post-translational modifications (PTMs) act as dynamic molecular mechanisms for controlling APE1 functionality. Interestingly, the N-terminal region of APE1 is a disordered portion functioning as an interface for protein binding, as an acceptor site for PTMs and as a target of proteolytic cleavage. We previously demonstrated a cytoplasmic accumulation of truncated APE1 in acute myeloid leukemia (AML) cells in association with a mutated form of nucleophosmin having aberrant cytoplasmic localization (NPM1c+). Here, we mapped the proteolytic sites of APE1 in AML cells at Lys31 and Lys32 and showed that substitution of Lys27, 31, 32 and 35 with alanine impairs proteolysis. We found that the loss of the APE1 N-terminal domain in AML cells is dependent on the proteasome, but not on granzyme A/K as described previously. The present work identified the proteasome as a contributing machinery involved in APE1 cleavage in AML cells, suggesting that acetylation can modulate this process.

scholarly journals Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

Blood ◽  
2012 ◽  
Vol 120 (4) ◽  
pp. 868-879 ◽  
Author(s):  
John Anto Pulikkan ◽  
Dmitri Madera ◽  
Liting Xue ◽  
Paul Bradley ◽  
Sean Francis Landrette ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Virus ◽  
Myeloproliferative Disorders ◽  
Chromosome Translocation ◽  
Leukemic Cells ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Downstream Signaling ◽  
Acute Myeloid

Abstract Oncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by thrombopoietin (THPO), is mutated in myeloproliferative disorders but rarely in AML. Here we show that wild-type MPL expression is increased in a fraction of human AML samples expressing RUNX1-ETO, a fusion protein created by chromosome translocation t(8;21), and that up-regulation of Mpl expression in mice induces AML when coexpressed with RUNX1-ETO. The leukemic cells are sensitive to THPO, activating survival and proliferative responses. Mpl expression is not regulated by RUNX1-ETO in mouse hematopoietic progenitors or leukemic cells. Moreover, we find that activation of PI3K/AKT but not ERK/MEK pathway is a critical mediator of the MPL-directed antiapoptotic function in leukemic cells. Hence, this study provides evidence that up-regulation of wild-type MPL levels promotes leukemia development and maintenance through activation of the PI3K/AKT axis, and suggests that inhibitors of this axis could be effective for treatment of MPL-positive AML.

scholarly journals A Chimeric Ty3/Moloney Murine Leukemia Virus Integrase Protein Is Active In Vivo

1998 ◽  
Vol 72 (5) ◽  
pp. 4297-4307 ◽  
Author(s):  
Sandra L. Dildine ◽  
James Respess ◽  
Doug Jolly ◽  
Suzanne B. Sandmeyer
Keyword(s):  
Cell Line ◽  
Murine Leukemia Virus ◽  
Genomic Dna ◽  
Integration Site ◽  
Leukemia Virus ◽  
Moloney Murine Leukemia Virus ◽  
Packaging Cell Line ◽  
Terminal Domain ◽  
Murine Leukemia

ABSTRACT This report describes the results of experiments to determine whether chimeras between a retrovirus and portions of Ty3 are active in vivo. A chimera between Ty3 and a Neor-marked Moloney murine leukemia virus (M-MuLV) was constructed. The C-terminal domain of M-MuLV integrase (IN) was replaced with the C-terminal domain of Ty3 IN. The chimeric retroviruses were expressed from an amphotrophic envelope packaging cell line. The virus generated was used to infect the human fibrosarcoma cell line HT1080, and cells in which integration had occurred were selected by G418 resistance. Three independently integrated viruses were rescued. In each case, the C-terminal Ty3 IN sequences were maintained and short direct repeats of the genomic DNA flanked the integration site. Sequence analysis of the genomic DNA flanking the insertion did not identify a tRNA gene; therefore, these integration events did not have Ty3 position specificity. This study showed that IN sequences from the yeast retrovirus-like element Ty3 can substitute for M-MuLV IN sequences in the C-terminal domain and contribute to IN function in vivo. It is also one of the first in vivo demonstrations of activity of a retrovirus encoding an integrase chimera. Studies of chimeras between IN species with distinctive integration patterns should complement previous work by expanding our understanding of the roles of nonconserved domains.

scholarly journals Myelodysplastic syndromes and acute myeloid leukemia in cats infected with feline leukemia virus clone33 containing a unique long terminal repeat

2009 ◽  
Vol 124 (5) ◽  
pp. 1133-1141 ◽  
Author(s):  
Masaharu Hisasue ◽  
Naho Nagashima ◽  
Kazuo Nishigaki ◽  
Isao Fukuzawa ◽  
Shigeyoshi Ura ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Long Terminal Repeat ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Leukemia Virus ◽  
Terminal Repeat ◽  
Feline Leukemia Virus ◽  
Acute Myeloid
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