A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3793-3799 ◽  
Author(s):  
Xiao-Qiang Yan ◽  
Ulla Sarmiento ◽  
Yu Sun ◽  
Guo Huang ◽  
Jane Guo ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Early Stage ◽  
Lymphoproliferative Disease ◽  
Lymphoid Tissues ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Notch Ligand ◽  
Cell Fate Decisions ◽  
Multiple Organs

Abstract Notch receptors mediate cell-fate decisions through interaction with specific ligands during development. The biological role of a novel Notch ligand, Dll4, in mice was explored by reconstituting lethally irradiated mice with bone marrow (BM) cells transduced with Dll4 retroviral vector. White blood cell and lymphocyte counts in Dll4-overexpressing mice were reduced at the early stage of reconstitution but increased significantly at approximately 10 weeks after BM transplantation. BM, spleen, lymph nodes, and peripheral blood ofDll4-overexpressing mice contained predominantly CD4+CD8+ T cells and virtually lacked B cells. The Dll4-overexpressing mice eventually developed a lethal phenotype that was characterized by the progression of a T-cell lymphoproliferative disease (restricted to BM and lymphoid tissues) to transplantable monoclonal T-cell leukemia/lymphoma scattered to multiple organs. Results suggest that the interaction of Dll4with Notch1 may provide key signals for T-cell development.

scholarly journals Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells

2005 ◽  
Vol 201 (9) ◽  
pp. 1361-1366 ◽  
Author(s):  
Mari H. Dallas ◽  
Barbara Varnum-Finney ◽  
Colleen Delaney ◽  
Keizo Kato ◽  
Irwin D. Bernstein
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Fate ◽  
Precursor Cells ◽  
Hematopoietic Stem ◽  
Notch Ligand ◽  
Murine Bone Marrow ◽  
Cell Fate Decisions ◽  
Multiple Cell ◽  
B Cell Precursors

Notch signaling regulates multiple cell fate decisions by hematopoietic precursors. To address whether different amounts of Notch ligand influence lineage choices, we cultured murine bone marrow lin−Sca-1+c-kit+ cells with increasing densities of immobilized Delta1ext-IgG consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1. We found that relatively lower densities of Delta1ext-IgG enhanced the generation of Sca-1+c-kit+ cells, Thy1+CD25+ early T cell precursors, and B220+CD43−/lo cells that, when cocultured with OP9 stroma cells, differentiated into CD19+ early B cell precursors. Higher densities of Delta1ext-IgG also enhanced the generation of Sca-1+c-kit+ precursor cells and promoted the development of Thy1+CD25+ cells, but inhibited the development of B220+CD43−/lo cells. Analyses of further isolated precursor populations suggested that the enhanced generation of T and B cell precursors resulted from the effects on multipotent rather than lymphoid-committed precursors. The results demonstrate the density-dependent effects of Delta1 on fate decisions of hematopoietic precursors at multiple maturational stages and substantiate the previously unrecognized ability of Delta1 to enhance the development of both early B and T precursor cells.

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.

scholarly journals Polycomb-Dependent Epigenetic Landscape in Adult T Cell Leukemia (ATL); Providing Proof of Concept for Targeting EZH1/2 to Selectively Eliminate the HTLV-1 Infected Population

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 572-572 ◽  
Author(s):  
Makoto Yamagishi ◽  
Dai Fujikawa ◽  
Daisuke Honma ◽  
Nobuaki Adachi ◽  
Shota Nakagawa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Early Stage ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Dual Inhibitor ◽  
Adult T Cell Leukemia ◽  
Immortalized Cells ◽  
Epigenetic Disruption

Abstract Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell leukemia/lymphoma and is refractory to currently available combination chemotherapy. The unfavorable prognosis results from an inadequate understanding of how diseases are caused and maintained in human T-cell leukemia virus type I (HTLV-1)-infected individuals. To date, direct comprehensive analyses of leukemic cells have identified the intrinsic molecular hallmarks of ATL. Among these, polycomb group (PcG)-mediated epigenetic disruption has been known to be a crucial characteristic of ATL (Yamagishi et al., Cancer Cell, 2012). However, no attempt has been made to determine the global epigenomic status explaining the deregulated gene expression pattern specific to ATL. In this study, we performed integrative analyses of epigenome (n=3) and transcriptome (n=58) of primary ATL patient cells and corresponding normal CD4+ T cells to decipher the ATL-specific 'epigenetic-code' that was critical for cell identity. We found that PcG-mediated tri-methylation at histone H3Lys27 (H3K27me3) was significantly and frequently reprogrammed at over half of genes (53.8%) in ATL cells, the pattern of which appears distinct from other cancer types and PcG-dependent cell lineages such as ES cells and peripheral T lymphocytes. Large proportion of the abnormal gene downregulation occurred at an early stage of disease progression and was explained by the H3K27me3 accumulation. The global H3K27me3 alterations were involved in determination of key genes such as miR-31, CADM1, EVC1/2, CDKN1A, and NDRG2, which are essential for ATL cell survival and other cellular characteristics. In addition, PcG generated diverse outcomes by the remote regulation of a broad spectrum of gene regulators, including various transcription factors, miRNAs, epigenetic modifiers, and developmental genes. Thus, the emerging epigenomic landscape is a fundamental characteristic of ATL. Although EZH2 mutations conferring gain-of-function were undetected in ATL (0/50; 0%), EZH2 level was significantly upregulated and inversely correlated with H3K27me3 targets, indicating that the global alteration of H3K27me3 mark depends on the abundance of EZH2 and other core components of the polycomb repressive complex 2 (PRC2). We found that EZH2 was sensitive to promiscuous signaling network including NF-kB pathway and was functionally affected by HTLV-1 Tax through both NF-kB activation and direct association. The Tax-dependent immortalized cells showed H3K27me3 reprogramming that was significantly similar to that of ATL cells. Of note, the majority of epigenetic silencing has occurred in leukemic cells from indolent type ATL and also in HTLV-1-infected T cells from asymptomatic HTLV-1 carriers. Collectively, our results unveiled that epigenetic reprogramming arises at an early stage of ATL development. Tracing the epigenetic marks and expression patterns in samples obtained from patients of various diagnostic categories, as well as in other biologically relevant models has supported the efficacy and relevance of targeting PRC2. Relief of the cumulative methylation may restore the aberrant transcriptome to ideal expression signature, permitting favorable treatments. According to the expression profiling, EZH2 may represent the first-choice as a druggable target. In addition, peripheral T cells highly express EZH1 that compensates for the EZH2 functions. We found that simultaneous depletion of the two H3K27me3 writers EZH1 and EZH2 significantly diminished cellular H3K27me3 level and dramatically inhibited ATL cell growth compared with single depletion, suggesting that the compensatory actions of EZH1/2 may be critical for ATL. To selectively eliminate the ATL and HTLV-1-infetced populations, we have developed a novel EZH1/2 dual-inhibitor that shows strong inhibitory effects for both of EZH1 and EZH2. Treatment with the new drugs showed significant inhibitory effects on the ATL cell survival derived from patients. Interestingly, the dual-inhibitor reversed the epigenetic disruption and selectively eliminated leukemic and immortalized cells from HTLV-1 infected individuals. Collectively, this approach will achieve potent and selective synthetic lethality by targeting the regulators of H3K27me3 in aggressive and indolent ATL cells, as well as in clonally expanded infected cells, improving medical care and the prevention of disease onset. Disclosures Yamagishi: Daiichi Sankyo Co., Ltd.: Research Funding. Honma:Daiichi Sankyo Co., Ltd: Employment. Adachi:Daiichi Sankyo Co., Ltd: Employment. Araki:Daiichi Sankyo Co., Ltd.: Employment. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

scholarly journals Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1

Blood ◽  
2007 ◽  
Vol 109 (8) ◽  
pp. 3579-3587 ◽  
Author(s):  
Mari H. Dallas ◽  
Barbara Varnum-Finney ◽  
Paul J. Martin ◽  
Irwin D. Bernstein
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Hematopoietic Cell Transplantation ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Critical Role ◽  
Hematopoietic Progenitors ◽  
Notch Ligand ◽  
Cell Fate Decisions ◽  
T Cell Reconstitution

Abstract A physiologic role for Notch signaling in hematopoiesis has been clearly defined in lymphoid differentiation, with evidence suggesting a critical role in T-cell versus B-cell fate decisions. Previously, we demonstrated that activation of endogenous Notch receptors by culture of murine lin−Sca-1+c-kit+ (LSK) hematopoietic progenitors with exogenously presented Notch ligand, Delta1ext-IgG, consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1, promoted early T-cell differentiation and increased the number of progenitors capable of short-term lymphoid and myeloid reconstitution. Here we show that culture of LSK precursors with Delta1ext-IgG increases the number of progenitors that are able to rapidly repopulate the thymus and accelerate early T-cell reconstitution with a diversified T-cell receptor repertoire. Most of the early T-cell reconstitution originated from cells that expressed lymphoid-associated antigens: B220, Thy1, CD25, and/or IL7Rα, whereas the most efficient thymic repopulation on a per cell basis originated from the smaller number of cultured cells that did not express lymphoid-associated antigens. These findings demonstrate the potential of Delta1ext-IgG-cultured cells for accelerating early immune reconstitution after hematopoietic cell transplantation.

Dysregulation of Adult T-Cell Leukemia-Derived Factor (ADF)/Thioredoxin in HIV Infection: Loss of ADF High-Producer Cells in Lymphoid Tissues of AIDS Patients

1992 ◽  
Vol 8 (9) ◽  
pp. 1707-1715 ◽  
Author(s):  
HIROSHI MASUTANI ◽  
MAKOTO NAITO ◽  
KIYOSHI TAKAHASHI ◽  
TOSHIO HATTORI ◽  
ATSUSHI KOITO ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Lymphoid Tissues ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Aids Patients ◽  
Adult T Cell Leukemia

scholarly journals Clinical and laboratory features of Adult T-cell Leukemia/lymphoma (ATL): a study of 37 cases

2018 ◽  
Vol 49 (2) ◽  
pp. 75-84
Author(s):  
Cristiane da Silva Rodrigues de Araújo ◽  
Mirna Maira Bezerra Calazan do Carmo ◽  
Claudia de Alvarenga Maximo ◽  
Sílvia Maia Farias de Carvalho
Keyword(s):  
T Cell ◽  
Lymphoproliferative Disease ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
The Family ◽  
Acute Form ◽  
Serologic Screening

AbstractAdult T-cell leukemia/lymphoma (ATL) related to the human T-cell lymphotropic virus type I (HTLV-I) is a malignant lymphoproliferative disease. ATL is classified in four subtypes: lymphoma, acute, smoldering and chronic. We analyzed, retrospectively, 46 consecutive patients with T-cell disease with ATL diagnosed from 1995 to 2007. ATL diagnose was confirmed in 37 of these patients. There were 26 females and 11 males (70% vs 30%, respectively, p=0.014). The median age was 42 years old. Twenty-five were nonwhite and twelve were white (67.6% vs 32.4%, respectively, p=0.033).Twenty two patients had the acute form, eight had chronic form and seven had lymphomatous form. Two of them had osteolytic lesions. There were two cases with pulmonary infiltrates; one patient had ATL associated to Hansen’s disease. All cases had antibodies to HTLV-I confirmed by Western Blot, polymerase chain reaction (PCR) was performed in 22 cases. Flow cytometry revealed positivity for CD4 and CD25 in most cases. The mean and median overall survival time was 11.3 months and 2 months, respectively. The family´s study showed that 60% of the mothers were HTLV-I seropositive. These data emphasize the importance of a serologic screening for HTLV and immunophenotyping to differentiate ATL from others T-lymphoproliferative disorders.

scholarly journals Control of HTLV-1 Infection by Eliminating Envelope Protein-Positive Cells with Recombinant Vesicular Stomatitis Viruses Encoding HTLV-1 Primary Receptor

2017 ◽  
pp. JVI.01885-17 ◽  
Author(s):  
Kenta Tezuka ◽  
Kazu Okuma ◽  
Madoka Kuramitsu ◽  
Sahoko Matsuoka ◽  
Reiko Tanaka ◽  
...  
Keyword(s):  
T Cell ◽  
De Novo ◽  
Lymphoid Tissues ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Primary Receptor ◽  
Infected Cells ◽  
Vesicular Stomatitis ◽  
Vesicular Stomatitis Viruses

Human T-cell leukemia virus type 1 (HTLV-1) infection causes adult T-cell leukemia (ATL), which is frequently resistant to current available therapies and has a very poor prognosis. To prevent the development of ATL among carriers it is important to control HTLV-1–infected cells in infected individuals. Therefore, the establishment of novel therapies with drugs specifically targeting infected cells is urgently required. This study aimed to develop a potential therapy by generating recombinant vesicular stomatitis viruses (rVSVs) that lack an envelope glycoprotein G and instead encode HTLV-1 receptor(s) with human glucose transporter 1 (GLUT1), neuropilin 1 (NRP1), or heparan sulfate proteoglycans (HSPGs) including syndecan 1 (SDC1), designated as VSVΔG-GL, VSVΔG-NP, or VSVΔG-SD, respectively. In an attempt to enhance the infectivity of rVSV against HTLV-1–infected cells, we also constructed rVSVs with a combination of two or three receptor genes, designated as VSVΔG-GLN and VSVΔG-GLNS, respectively. The current study demonstrated VSVΔG-GL, VSVΔG-NP, VSVΔG-GLN, and VSVΔG-GLNS have tropism for HTLV-1 envelope (Env) expressing cells. Notably, the inoculation of VSVΔG-GL or VSVΔG-NP significantly eliminated HTLV-1–infected cells in the culture conditions. Furthermore, in an HTLV-1–infected humanized mouse model, VSVΔG-NP was capable of efficiently preventing HTLV-1–induced leukocytosis in the periphery and eliminating HTLV-1–infected Env-expressing cells in the lymphoid tissues. In summary, an rVSV engineered to express HTLV-1 primary receptor, especially human NRP1, may represent a drug candidate that has potential for the development of unique virotherapy against HTLV-1de novoinfection.IMPORTANCEAlthough several anti-ATL therapies are currently available, ATL is still frequently resistant to therapeutic approaches and its prognosis remains poor. Control ofde novoHTLV-1 infection or expansion of HTLV-1–infected cells in the carrier holds considerable promise for the prevention of ATL development. In this study, we developed rVSVs that specifically target and kill HTLV-1 Env-expressing cells (not ATL cells, which generally do not express Envin vivo) through replacement of the G gene with HTLV-1 receptor gene(s) in the VSV genome. Notably, an rVSV engineered to express human NRP1 controlled the number of HTLV-1–infected Env-expressing cellsin vitroandin vivo, suggesting the present approach may be a promising candidate for novel anti-HTLV-1 virotherapy in HTLV-1 carriers, including as a prophylactic treatment against the development of ATL.

Density-Dependent Regulation of Hematopoietic Stem Cell Fate by the Notch Ligand, Delta1.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1700-1700
Author(s):  
Mari H. Dallas ◽  
Colleen Delaney ◽  
Barbara Varnum-Finney ◽  
Irwin D. Bernstein
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Myeloid Differentiation ◽  
Hematopoietic Stem ◽  
Notch Ligand ◽  
Cell Fate Decisions ◽  
Human Igg1 ◽  
Cell Commitment ◽  
Number Of Cells

Notch signaling regulates multiple cell fate decisions by hematopoietic precursors. Previously, we found that endogenous Notch signaling in cultures of murine hematopoietic precursors (Lin-Sca-1+ c-Kit+) leads to a multi-log increase in the number of Sca-1+ c-Kit+ cells, inhibition of myeloid differentiation, and promotion of T/NK differentiation. To activate Notch signaling in those studies, a single dose (10μg/ml) of engineered Notch ligand consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1 (Delta1ext-IgG) was immobilized to the plastic tissue culture surface. To investigate quantitative effects of Notch signaling, bone marrow Lin-Sca-1+ c-Kit+ (LSK) cells were cultured with plates coated with increasing concentrations of Delta1ext-IgG in media supplemented with 20% FBS, SCF (100 ng/mL), Flt3L (100 ng/mL), IL6 (100ng/mL) and IL11 (10ng/mL). LSK cells cultured for 14 days with control human IgG1 underwent terminal myeloid differentiation (determined by expression of GR1 and F4/80) with no further increase in cell number, whereas at all densities of Delta1ext-IgG there was approximately a 3 log greater number of cells than in control cultures. Furthermore, the portion of cells that maintained Sca-1 and c-Kit expression increased at greater densities of Delta1ext-IgG (10%, 32%, 77%, 71%, 71% and 71% for plates coated with ligand at 0.6, 1.25, 2.5, 5, 10 and 20 μg/ml, respectively, and 5% for human IgG1 control at 10μg/ml), whereas the portion of cells undergoing myeloid differentiation decreased at greater ligand densities (48%, 33%, 5%, 3%, 3% and 3% respectively, and 40% for control). In contrast, a substantial increase in the portion of cells expressing B220+ was observed at relatively low densities of Delta1ext-IgG (30% at 0.6 μg/ml and 19% at 1.25 μg/ml) compared to control (4%), but was no longer evident with further increases in ligand density (1.8%, 2%, 1.2%, m1.6% at 2.5, 5, 10 and 20 μg/ml respectively). Furthermore, promotion of early T cell differentiation was observed in ligand containing cultures with the generation of increased number of cells co-expressing Thy1.2 and CD25 (14%, 24%, 22% and 24% at 2.5, 5, 10 and 20 μg/ml respectively). Further evidence for T cell commitment was established by quantitative RT-PCR in which increased expression of CD3ε and pre-Tα was observed by 28 days of culture. Thus these studies demonstrate that culture with different densities of the Notch ligand, Delta1ext-IgG results in differential cell fate outcome with inhibition of myeloid differentiation and promotion of early T cell induction that is maximal at high ligand densities and of B220+ cells at relatively lower densities.

Sign in / Sign up

Export Citation Format

Share Document