IL2/IL-4, OX40L and FDC-like cell line support the in vitro tumor cell growth of adult T-cell leukemia/lymphoma

Abstract Interleukin 2 (IL-2) receptor/Tac antigen is abnormally expressed on cells of patients with adult T cell leukemia (ATL) caused by infection with human T lymphotropic virus type I (HTLV-I). Twenty-five patients with ATL were examined to determine whether their leukemic cells continued to show IL-2-dependent proliferation. In 21 patients, the in vitro proliferation of HTLV-I-infected nonleukemic T cell clones was found to be dependent on IL-2. However, clonality analysis based on T cell receptor gene rearrangement profiles and the site of HTLV-I provirus integration revealed IL-2-dependent growth in leukemic cells in four patients with ATL. These results provide evidence for the IL-2- dependent proliferation of leukemic cells in some ATL patients.

Download Full-text

Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases

Life ◽

10.3390/life11020127 ◽

2021 ◽

Vol 11 (2) ◽

pp. 127

Author(s):

Norbert Kassay ◽

János András Mótyán ◽

Krisztina Matúz ◽

Mária Golda ◽

József Tőzsér

Keyword(s):

T Cell ◽

Biochemical Characterization ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

T Cell Leukemia Virus

The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1′ subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.

Download Full-text

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

Blood ◽

10.1182/blood-2020-140060 ◽

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.

Download Full-text

N-cadherin expression in human adult T-cell leukemia cell line

Archives of Dermatological Research ◽

10.1007/s004030050294 ◽

1998 ◽

Vol 290 (4) ◽

pp. 223-225 ◽

Cited By ~ 3

Author(s):

N. Matsuyoshi ◽

Ken-ichi Toda ◽

Sadao Imamura

Keyword(s):

T Cell ◽

Cell Line ◽

Leukemia Cell ◽

Leukemia Cell Line ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Human Adult

Download Full-text

A New Guaiane-type Sesquiterpenoid from a Bornean Soft Coral, Xenia stellifera

Natural Product Communications ◽

10.1177/1934578x1801300105 ◽

2018 ◽

Vol 13 (1) ◽

pp. 1934578X1801300 ◽

Cited By ~ 2

Author(s):

Chin-Soon Phan ◽

Takashi Kamada ◽

Takahiro Ishii ◽

Toshiyuki Hamada ◽

Charles Santhanaraju Vairappan

Keyword(s):

Biological Activity ◽

T Cell ◽

Cell Line ◽

Spectroscopic Data ◽

Soft Coral ◽

Leukemia Cell ◽

Leukemia Cell Line ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

A new guaiane-type sesquiterpenoid, 10β- O-methyl-1αH,5αH-guaia-6-en-4β-ol (1) along with two known compounds, 10- O -methyl alismoxide (2) and alismoxide (3) were isolated from a population of Bornean soft coral Xenia stellifera. The structure of this metabolite was elucidated based on spectroscopic data such as NMR and HRESIMS. These compounds were evaluated for their biological activity against adult T-cell leukemia cell line.

Download Full-text

Leukemic cells from some adult T-cell leukemia patients proliferate in response to interleukin-4

Blood ◽

10.1182/blood.v72.4.1182.1182 ◽

1988 ◽

Vol 72 (4) ◽

pp. 1182-1186 ◽

Cited By ~ 33

Author(s):

T Uchiyama ◽

M Kamio ◽

T Kodaka ◽

S Tamori ◽

S Fukuhara ◽

...

Keyword(s):

T Cell ◽

Cell Growth ◽

Proliferative Response ◽

Interleukin 2 ◽

Leukemic Cells ◽

Interleukin 4 ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Receptor System ◽

Adult T Cell Leukemia

Abstract The proliferative response of fresh peripheral blood leukemic cells from eight adult T cell leukemia (ATL) patients to interleukin-4 (IL-4) was studied to determine the possibility that the IL-4-mediated T-cell growth pathway is involved in the cell growth of leukemic cells in ATL. Resting lymphocytes from ten normal individuals did not proliferate in response to IL-4. Leukemic cells from two ATL patients did not respond to interleukin-2 (IL-2) or IL-4. Leukemic cells from two patients did respond to IL-2, but not to IL-4. In contrast, a strong proliferative response was observed in the IL-4 culture, but not in the IL-2 culture in the remaining four patients. Chromosome analysis of mitotic cells, performed in one of four patients, confirmed that the cells dividing in response to IL-4 were leukemic cells, but not activated normal lymphocytes. These results indicate the activation of IL-4/IL-4 receptor system in leukemic cells from some ATL patients and suggest the possible involvement of the system in the proliferation of leukemic cells and the leukemogenesis in ATL.

Download Full-text

Clinical and in vitro resistance to bexarotene in adult T-cell leukemia: loss of RXR-α receptor

Blood ◽

10.1182/blood-2008-03-141424 ◽

2008 ◽

Vol 112 (6) ◽

pp. 2484-2488 ◽

Cited By ~ 7

Author(s):

Julie H. Lin ◽

Ellen J. Kim ◽

Anand Bansal ◽

John Seykora ◽

Stephen K. Richardson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Peripheral Blood ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

First Case ◽

Induced Apoptosis ◽

Resistant Cells

Abstract The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)-α2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor (RXR) subunits, RXR-α and RXR-β, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-α and RXR-β by resistant cells. We assessed RXR-α and RXR-β expression by Western blot analysis and found that resistant cells had significantly decreased RXR-α expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-α receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.

Download Full-text