NOTCH1-Induced T-Cell Leukemia in Transgenic Zebrafish.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1825-1825
Author(s):  
Jihua Chen ◽  
Cicely Jette ◽  
John P. Kanki ◽  
Jon Aster ◽  
A. Thomas Look ◽  
...  
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Genetic Modifier ◽  
Chromosome Translocation ◽  
Lymphoproliferative Disease ◽  
Transgenic Zebrafish ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Zebrafish Model

Abstract Activating mutations in the NOTCH1 gene have been found in about 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL). In order to study the molecular mechanisms by which altered Notch signaling induces leukemia, a zebrafish model of NOTCH1-induced T-cell leukemia was generated using TAN-1, the NOTCH1 oncogene generated by the t(7;9)(q34;q34.3) chromosome translocation associated with human T-ALL. Seven of sixteen mosaic fish developed a T cell lymphoproliferative disease at about 5 months. These neoplastic cells extensively invaded tissues throughout the fish and caused an aggressive and lethal leukemia when transplanted into irradiated recipient fish. A stable transgenic fish line was then generated, which also develops leukemia, but with a longer latency for leukemia onset. This longer latency allowed crosses to be done to evaluate potential genetic interactions between NOTCH1 and other T-ALL oncogenes. Interestingly, LMO2 did not cooperate with NOTCH1 to induce T-ALL, while bcl2 had dramatic effects on latency and progression of T-ALL in this zebrafish model. These results suggest that the transforming functions of NOTCH1 and LMO2 may be redundant, while the functions of NOTCH1 and bcl2 are highly complementary. The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL.

Overexpression of hTLX3 in Association with Mutant IL7Rα Is Sufficient to Generate T-ALL In Vivo and to Transform Thymocytes in Vitro

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Gisele Olinto Libanio Rodrigues ◽  
Julie Hixon ◽  
Hila Winer ◽  
Erica Matich ◽  
Caroline Andrews ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Lymphoblastic Leukemia ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Counts

Mutations of the IL-7Rα chain occur in approximately 10% of pediatric T-cell acute lymphoblastic leukemia cases. While we have shown that mutant IL7Ra is sufficient to transform an immortalized thymocyte cell line, mutation of IL7Ra alone was insufficient to cause transformation of primary T cells, suggesting that additional genetic lesions may be present contributing to initiate leukemia. Studies addressing the combinations of mutant IL7Ra plus TLX3 overexpression indicates in vitro growth advantage, suggesting this gene as potential collaborative candidate. Furthermore, patients with mutated IL7R were more likely to have TLX3 or HOXA subgroup leukemia. We sought to determine whether combination of mutant hIL7Ra plus TLX3 overexpression is sufficient to generate T-cell leukemia in vivo. Double negative thymocytes were isolated from C57BL/6J mice and transduced with retroviral vectors containing mutant hIL7R plus hTLX3, or the genes alone. The combination mutant hIL7R wild type and hTLX3 was also tested. Transduced thymocytes were cultured on the OP9-DL4 bone marrow stromal cell line for 5-13 days and accessed for expression of transduced constructs and then injected into sublethally irradiated Rag-/- mice. Mice were euthanized at onset of clinical signs, and cells were immunophenotyped by flow cytometry. Thymocytes transduced with muthIL-7R-hTLX3 transformed to cytokine-independent growth and expanded over 30 days in the absence of all cytokines. Mice injected with muthIL7R-hTLX3 cells, but not the controls (wthIL7R-hTLX3or mutIL7R alone) developed leukemia approximately 3 weeks post injection, characterized by GFP expressing T-cells in blood, spleen, liver, lymph nodes and bone marrow. Furthermore, leukemic mice had increased white blood cell counts and presented with splenomegaly. Phenotypic analysis revealed a higher CD4-CD8- T cell population in the blood, bone marrow, liver and spleen compared in the mutant hIL7R + hTLX3 mice compared with mice injected with mutant IL7R alone indicating that the resulting leukemia from the combination mutant hIL7R plus hTLX3 shows early arrest in T-cell development. Taken together, these data show that oncogenic IL7R activation is sufficient for cooperation with hTLX3 in ex vivo thymocyte cell transformation, and that cells expressing the combination muthIL7R-hTLX3 is sufficient to trigger T-cell leukemia in vivo. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein.

1990 ◽  
Vol 9 (2) ◽  
pp. 415-424 ◽  
Author(s):  
Q. Chen ◽  
J.T. Cheng ◽  
L.H. Tasi ◽  
N. Schneider ◽  
G. Buchanan ◽  
...  
Keyword(s):  
T Cell ◽  
Chromosome Translocation ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Helix Loop Helix

Myc-Induced T Cell Leukemia in Transgenic Zebrafish

Science ◽  
2003 ◽  
Vol 299 (5608) ◽  
pp. 887-890 ◽  
Author(s):  
D. M. Langenau
Keyword(s):  
T Cell ◽  
Transgenic Zebrafish ◽  
T Cell Leukemia ◽  
Cell Leukemia

Bcl2 Accelerates Onset but Not Progression of MYC-Induced T-Cell Leukemia in Transgenic Zebrafish.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1829-1829
Author(s):  
Hui Feng ◽  
David M. Langenau ◽  
Jennifer A. Kilgore ◽  
Andre Quinkertz ◽  
Cicely A. Jette ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Fluorescent Protein ◽  
Lymphoblastic Leukemia ◽  
Disease Onset ◽  
Transgenic Fish ◽  
Transgenic Animals ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Transgenic Embryos

Abstract MYC is a potent proto-oncogene aberrantly expressed in over 70% of human cancers. Our laboratory has previously generated transgenic zebrafish models that overexpress the mouse c-Myc gene fused to green fluorescent protein and develop T-cell Acute Lymphoblastic Leukemia (T-ALL) that recapitulates the human disease both molecularly and pathologically. These previous models have been limited by the inability to breed non-conditional transgenic animals due to disease onset prior to sexual maturity and by the low disease penetrance when conditional transgenic embryos are injected with Cre RNA. In order to improve these zebrafish T-ALL models to make modifier screens feasible, we have generated a new stable Cre transgenic line in which Cre expression is regulated by a heat-shock promoter, and have established a conditional compound transgenic zebrafish model by breeding this pzhsp70-Cre line with conditional rag2-lox-dsRED2-lox-EGFP-mMyc transgenic fish. Upon heat-shock treatment, 81% of compound transgenic fish developed tumor by 197 days of life (mean latency: 120 ± 43 days). Using this model, we showed that overexpression of zebrafish Bcl-2 strikingly accelerates the disease onset, suggesting that suppression of apoptosis is critical for zebrafish Myc-induced tumorigenesis and serving as a proof of principle for subsequent modifier screens. Paradoxically, overexpression of Bcl-2 delays the progression of T-ALL, implying functional roles for Bcl-2 in addition to the inhibition of apoptosis.

scholarly journals Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Blood ◽  
2017 ◽  
Vol 129 (9) ◽  
pp. 1071-1081 ◽  
Author(s):  
Toshiki Watanabe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
New Findings

Abstract Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2863-2870 ◽  
Author(s):  
Edwin Bremer ◽  
Bram ten Cate ◽  
Douwe F. Samplonius ◽  
Lou F. M. H. de Leij ◽  
Wijnand Helfrich
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Tumor Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Single Chain ◽  
Tumoricidal Activity ◽  
Variable Regions

AbstractAgonistic anti-Fas antibodies and multimeric recombinant Fas ligand (FasL) preparations show high tumoricidal activity against leukemic cells, but are unsuitable for clinical application due to unacceptable systemic toxicity. Consequently, new antileukemia strategies based on Fas activation have to meet the criterion of strictly localized action at the tumor-cell surface. Recent insight into the FasL/Fas system has revealed that soluble homotrimeric FasL (sFasL) is in fact nontoxic to normal cells, but also lacks tumoricidal activity. We report on a novel fusion protein, designated scFvCD7:sFasL, that is designed to have leukemia-restricted activity. ScFvCD7:sFasL consists of sFasL genetically linked to a high-affinity single-chain fragment of variable regions (scFv) antibody fragment specific for the T-cell leukemia-associated antigen CD7. Soluble homotrimeric scFvCD7:sFasL is inactive and acquires tumoricidal activity only after specific binding to tumor cell-surface-expressed CD7. Treatment of T-cell acute lymphoblastic leukemia (T-ALL) cell lines and patient-derived T-ALL, peripheral T-cell lymphoma (PTCL), and CD7-positive acute myeloid leukemia (AML) cells with homotrimeric scFvCD7:sFasL revealed potent CD7-restricted induction of apoptosis that was augmented by conventional drugs, farnesyl transferase inhibitor L-744832, and the proteasome inhibitor bortezomib (Velcade; Millenium, Cambridge, MA). Importantly, identical treatment did not affect normal human peripheral-blood lymphocytes (PBLs) and endothelial cells, with only moderate apoptosis in interleukin-2 (IL-2)/CD3-activated T cells. CD7-restricted activation of Fas in T-cell leukemic cells by scFvCD7:sFasL revitalizes interest in the applicability of Fas signaling in leukemia therapy.

Mutational Analysis of NOTCH1 Gene in Mature T-Cell Leukemia/Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4656-4656
Author(s):  
Daisuke Shimizu ◽  
Tomohiko Taki ◽  
Atae Utsunomiya ◽  
Hitoshi Nakagawa ◽  
Kenichi Nomura ◽  
...  
Keyword(s):  
T Cell ◽  
High Performance ◽  
Mutational Analysis ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Rearrangements ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Prolymphocytic Leukemia ◽  
Adult T Cell Leukemia ◽  
Non Hodgkin Lymphoma

Abstract A somatic mutation of the NOTCH1 gene is frequently observed in T-cell acute lymphoblastic leukemia (T-ALL) of immature T-cell leukemia, but its prevalence in mature T-cell leukemia/lymphoma remains unknown. T-cell non-Hodgkin lymphomas (T-NHL) are relatively uncommon malignancies that represent approximately 12% of all lymphomas. The current WHO/EORTC classification recognizes 9 distinct clinicopathologic peripheral T-NHLs. The identification of genetic abnormalities and chromosomal rearrangements has been helpful in recognizing and defining lymphoma entities according to the WHO classification. However, the molecular changes that could play a role in leukemogenesis and progression remain unknown. NOTCH1 gene mutation was analyzed in 53 mature T-cell leukemia/lymphoma in adults, comprising 21 with adult T-cell leukemia (ATL), 25 with T-cell non-Hodgkin lymphoma (T-NHL), seven with T-cell prolymphocytic leukemia (T-PLL). We analyzed the hotspots of the NOTCH1 activating mutation in T-ALL cases located in exons 26 and 27, which encodes the N-terminal and C-terminal region of the heterodimerization (HD-N, HD-C) domain, and in exon 34, which encodes the PEST domain and terminal activation domain (TAD). Mutation detection in these two locations was performed by means of PCR-based denaturing high-performance liquid chromatography (dHPLC) using a WAVE DNA fragment analysis system followed by sequencing. We detected a nonsense mutation, C7249T, resulting in Q2417X, in an ATL patient, and a missense mutation, A6955G, resulting in M2319V, as well as a 3-bp deletion between 7234 and 7236 that resulted in deletion of the proline at codon 2412 in the same allele in a T-NHL, peripheral T-cell lymphoma, unspecified (PTCL-u), patient. NOTCH1 mutation was infrequent in mature T-cell leukemia/lymphoma, but NOTCH1 may be involved in leukemogenesis associated with a variety of T-cell leukemia/lymphoma rather than only with T-ALL. Figure 1. (A) ATL case No.9, (B) T-NHL case No.38, (C) T-NHL case No.38 Figure 1. (A) ATL case No.9, (B) T-NHL case No.38, (C) T-NHL case No.38

Galactorrhea and Acute Lymphoblastic T-Cell Leukemia: A Case Presentation and Evaluation of the Role of Prolactin

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4828-4828
Author(s):  
Allison C Grimes
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Rate ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Case Presentation ◽  
Underlying Causes ◽  
Multi Agent

Abstract Abstract 4828 Acute lymphoblastic T-cell leukemia (T-ALL) accounts for nearly 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL has conferred a worse prognosis than other forms of ALL. Although multi-agent pulse chemotherapy has improved EFS over the past several decades, the lack of clinical or laboratory based prognosticators as well as high rate of relapse have remained barriers in management. Described is a case of acute lymphoblastic T-cell leukemia in a previously healthy sixteen-year-old girl initially presenting with galactorrhea and hyperprolactinemia without evidence of CNS infiltrate. Although galactorrhea has been described in a few adults as an initial presentation of acute myeloginous leukemia (AML) and a single adult case of T-cell lymphoma, to date there has been no association with childhood cancers or T-ALL in particular. Hypothesized in AML cases as a rare paraneoplastic phenomenon, this case explores this theory and employs direct prolactin staining of tumor cell cytoplasm, serial prolactin monitoring throughout treatment, and investigation into underlying causes for hyperprolactinemia in the context of T-ALL. The possibilities for prolactin as a novel tumor marker are explored. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antitumor Effect of Sugar-Modified Cytosine Nucleosides on Growth of Adult T-Cell Leukemia Cells in Mice

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 658
Author(s):  
Naoyoshi Maeda ◽  
Akira Matsuda ◽  
Satoko Otsuguro ◽  
Masahiko Takahashi ◽  
Masahiro Fujii ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Drug ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Nog Mice

Adult T-cell leukemia (ATL) is a CD4+ T-cell neoplasm caused by human T-cell leukemia virus type I. As the prognosis for patients with ATL remains extremely poor due to resistance to conventional chemotherapy regimens, introduction of novel therapeutic agents is needed. Previous studies have reported that nucleosides 2′-deoxy-2′-methylidenecytidine (DMDC) and its derivative 2′-deoxy-2′-methylidene-5-fluorocytidine (FDMDC) exhibit antitumor activities in T-cell acute lymphoblastic leukemia (T-ALL) and solid tumor cell lines. Another nucleoside, 1-(2-azido-2-deoxy-β-D-arabinofuranosyl)cytosine (cytarazid), is considered a therapeutic drug with antitumor activity in human solid tumors. In this study, we investigated the effects of these nucleosides on cell growth in vitro and in vivo using relevant leukemia cell lines and NOD/Shi-scid, IL-2Rgnull (NOG) mice, respectively. The nucleosides demonstrated significant cytotoxic effects in ATL and T-ALL cell lines. Intraperitoneal administration of FDMDC and DMDC into tumor-bearing NOG mice resulted in significant suppression of tumor growth without lethal side effects. Our findings support a therapeutic application of these nucleosides against tumor progression by targeting DNA polymerase-dependent DNA synthesis in patients with ATL.

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