Loss of the INK4A Locus Accelerates tal1/scl-Induced Leukemia in Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3495-3495
Author(s):  
Jennifer A. Calvo ◽  
Michelle Kelliher
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Transgenic Mice ◽  
Median Survival ◽  
S Phase ◽  
Bhlh Transcription Factor ◽  
Human Leukemia ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Wild Type

Abstract Tal1/scl, a basic helix-loop-helix (bHLH) transcription factor essential for hematopoiesis and vasculogenesis, is also found misexpressed in patients with T cell acute lymphoblastic leukemia (T-ALL). In our mouse model of tal1/scl-induced disease, mice develop T cell leukemia after a long latency, suggesting that additional mutations are required for leukemogenesis. In T-ALL patients, the INK4a locus, which encodes both p14ARF and p16INK4a, is often found mutated or methylated, suggesting that loss of p16INK4A/p14ARF expression contributes to the development of T-ALL. Similarly, we fail to detect p16INK4A/p19ARF expression in our mouse tal1/scl leukemic cells. To determine if the loss of INK4a cooperates with tal1/scl to induce leukemia, we mated our tal1/scl transgenic mice to INK4a −/− mice to generate a cohort of tal1/scl/INK4a+/− mice. Mice heterozygous for INK4a are healthy and are not predisposed to the development of leukemia. In contrast, tal1/scl/INK4a+/− mice develop T cell leukemia at an accelerated rate, within a median survival period of 110 days, compared to a median survival of 352 days for the tal1/scl transgenic mice, which are wild type with respect to INK4a. Taken together, these data suggest that mutation of the INK4a locus contributes to tal1/scl-mediated leukemogenesis in mice, similar to the widespread deletion of the INK4a/ARF locus observed in TAL1/SCL-expressing human leukemia (Ferrando, 2002). BrdU labeling of preleukemic tal1/scl thymocytes reveals a 41% increase in the percentage of thymocytes in S phase of the cell cycle, suggesting that tal1/scl may stimulate cell cycle progression. In contrast to wild type thymocytes which exhibit 14.5% (±1.5) of cells in S phase, 24.5% (± 2.9) of preleukemic tal1/scl thymocytes are found in S phase (p<0.05, n=4). Moreover, an increase in the sub-G1 population is also observed in the tal1/scl preleukemic thymus. Preliminary cell cycle analysis of tal1/scl/INK4a−/− thymocytes reveals a decrease in the sub-G1 population, suggesting that the absence of the INK4a locus may contribute to tal1/scl leukemogenesis, in part, by inhibiting the tal1/scl-induced apoptosis.

scholarly journals Stimulation of Cyclin-Dependent Kinase Activity and G1- to S-Phase Transition in Human Lymphocytes by the Human T-Cell Leukemia/Lymphotropic Virus Type 1 Tax Protein

1998 ◽  
Vol 72 (1) ◽  
pp. 633-640 ◽  
Author(s):  
Iris Schmitt ◽  
Oliver Rosin ◽  
Peter Rohwer ◽  
Manfred Gossen ◽  
Ralph Grassmann
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
S Phase ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Human T Cell

ABSTRACT The human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) induces a malignant lymphocytic disease. The HTLV-1 transactivator protein, Tax, is believed to be crucial for the development of the disease since it is transforming in vitro and induces tumors in transgenic animals. Although the transcriptional modulation of viral and cellular gene expression by Tax has been analyzed thoroughly, it has remained unclear how the Tax functions act on the cell cycle of primary T cells. To investigate the mechanism of Tax-mediated T-cell stimulation, we transduced primary human cord blood T cells with a conditional, tetracycline repressor-based tax expression system. Permanent Tax expression results in an abnormal proliferation of T cells which closely resemble HTLV-1-infected lymphocytes. Suppression of Tax synthesis stopped lymphocyte growth and caused cell cycle arrest in the G1 phase. Upon reinduction oftax expression, the arrested cells entered the S phase. This showed that Tax has mitogenic activity, which is required for stimulating the G1- to S-phase transition of immortalized lymphocytes. In mammalian cells, the G1-phase progression is controlled by the serial activation of several cyclin-dependent kinases (Cdks), starting with Cdk4 and Cdk6. In the presence of Tax, both Cdk4 and Cdk6 were activated. The suppression of Tax synthesis, however, resulted in a significant reduction of the Cdk4 and Cdk6 activities but did not influence the expression of Cdk4, Cdk6, or cognate D-type cyclin proteins. These data suggest that Tax induces Cdk4 and Cdk6 activity in primary human T lymphocytes; this Cdk activation is likely to account for the mitogenic Tax effect and for the abnormal T-cell proliferation of HTLV-1-infected lymphocytes.

scholarly journals Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Christophe Nicot
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Tumor Suppressors ◽  
Epigenetic Mechanisms ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Cycle Arrest

Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I.

scholarly journals Human T-Cell Leukemia Virus Type 1 Infection Leads to Arrest in the G1 Phase of the Cell Cycle

2008 ◽  
Vol 82 (17) ◽  
pp. 8442-8455 ◽  
Author(s):  
Meihong Liu ◽  
Liangpeng Yang ◽  
Ling Zhang ◽  
Baoying Liu ◽  
Randall Merling ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACT Infection by the human T-cell leukemia virus type 1 (HTLV-1) is thought to cause dysregulated T-cell proliferation, which in turn leads to adult T-cell leukemia/lymphoma. Early cellular changes after HTLV-1 infection have been difficult to study due to the poorly infectious nature of HTLV-1 and the need for cell-to-cell contact for HTLV-1 transmission. Using a series of reporter systems, we show that HeLa cells cease proliferation within one or two division cycles after infection by HTLV-1 or transduction of the HTLV-1 tax gene. HTLV-1-infected HeLa cells, like their tax-transduced counterparts, expressed high levels of p21 CIP1/WAF1 and p27 KIP1 , developed mitotic abnormalities, and became arrested in G1 in senescence. In contrast, cells of a human osteosarcoma lineage (HOS) continued to divide after HTLV-1 infection or Tax expression, albeit at a reduced growth rate and with mitotic aberrations. Unique to HOS cells is the dramatic reduction of p21 CIP1/WAF1 and p27 KIP1 expression, which is in part associated with the constitutive activation of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway. The loss of p21 CIP1/WAF1 and p27 KIP1 in HOS cells apparently allows HTLV-1- and Tax-induced G1 arrest to be bypassed. Finally, HTLV-1 infection and Tax expression also cause human SupT1 T cells to arrest in the G1 phase of the cell cycle. These results suggest that productive HTLV-1 infection ordinarily leads to Tax-mediated G1 arrest. However, T cells containing somatic mutations that inactivate p21 CIP1/WAF1 and p27 KIP1 may continue to proliferate after HTLV-1 infection and Tax expression. These infected cells can expand clonally, accumulate additional chromosomal abnormalities, and progress to cancer.

Anti-Adult T-Cell Leukemia Effects of a Novel Synthetic Retinoid, Am80 (Tamibarotene) through Inhibition of NF-κB.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2525-2525
Author(s):  
Tetsuro Nakazato ◽  
Chie Ishikawa ◽  
Taeko Okudaira ◽  
Mariko Tomita ◽  
Naoki Mori
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
T Cell ◽  
Cell Lines ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Synthetic Retinoid ◽  
T Cell Lines

Abstract Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type I (HTLV-I) and remains incurable. Retinoid is a collective term for compounds, which bind to and activate retinoic acid receptors (RARα, β, γ and RXRα, β, γ), members of nuclear hormone receptor superfamily. It is involved in cell differentiation, morphogenesis, proliferation, and anti-neoplastic processes. The most important endogenous retinoid is all-trans-retinoic acid (ATRA), which is an RARα, β, and γ ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and adult T-cell leukemia (ATL). Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARα- and RARβ-specific (but RARγ- and RXRs-nonbinding) synthetic retinoid that is expected to overcome ATRA resistance, because of several times more potent differentiation activity than ATRA and sustained plasma level during continuous administration due to a lower affinity for cellular retinoic acid binding protein. On this background, we examined the inhibitory effect of Am80 on HTLV-I-infected T-cell lines and primary ATL cells. Am80 showed little growth inhibition of peripheral blood mononuclear cells, but it markedly inhibited the growth of both HTLV-I-infected T-cell lines and primary ATL cells. Am 80 could arrest cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. The NF-κB pathway is critical for the immortalization and survival of HTLV-I-infected T cells. Therefore, NF-κB pathway was examined as potential targets of Am80 signaling. Am80 significantly inhibited phosphorylation of IκBα and NF-κB-DNA binding, in conjunction with the reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Furthermore, in animal studies, treatment with Am80 produced partial inhibition of growth of tumors of an HTLV-I-infected T-cell line transplanted subcutaneously in severe combined immunodeficient mice. These findings clearly demonstrate that Am80 is a potential inhibitor of NF-κB in ATL cells, and might be a useful therapeutic agent against ATL.

Cell Cycle Deregulation Determines Acute Transformation In Chronic Type Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 845-845
Author(s):  
Noriaki Yoshida ◽  
Kennosuke Karube ◽  
Atae Utsunomiya ◽  
Kunihiro Tsukasaki ◽  
Yoshitaka Imaizumi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Lines ◽  
P Value ◽  
Acute Type ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Chronic Type ◽  
Adult T Cell Leukemia ◽  
Oligo Array

Abstract Introduction Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1-induced neoplasm with four clinical subtypes; acute, lymphoma, chronic and smoldering. Although chronic and smoldering subtypes are regarded as indolent ATL, about half of these cases progress to acute type ATL and subsequent death. Therefore, cases of indolent ATL also have poor prognosis and acute transformation is a predictive indicator for patients with indolent ATL. However, the molecular pathogenesis of acute transformation remains unknown. In the present study, oligo-array comparative genomic hybridization (CGH) and comprehensive gene-expression profiling (GEP) were applied to 27 and 35 cases of chronic and acute type ATL, respectively, in an effort to delineate the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation. Materials and Methods All DNA and RNA used in this study were extracted from purified CD4-positive cells. Oligo-array CGH analyses and comprehensive GEP analyses were performed on 27 and 35 cases of chronic and acute type ATL, respectively. Subsequently, we established Tet-OFF ATL cell lines for functional analyses. Results Oligo-array CGH revealed that genomic loss of 9p21.3 was significantly characteristic of acute type ATL, but not chronic type ATL (p-value= 0.039). Although the minimal common deleted region of 9p21.3 contained MTAP, CDKN2A and CDKN2B, the expression level of only CDKN2A was reduced with genomic loss of 9p21.3 (Figure 1). Moreover, analysis of serial samples of a chronic type ATL patient showing acute transformation also revealed that reduction of CDKN2A expression by 9p21.3 loss was associated with acute transformation in this case. CDKN2A contains two known variants, INK4a and ARF. Re-expression of INK4a and ARF suppressed proliferation of Tet-OFF ATL cell lines, while the suppression efficiency of INK4a was stronger than that of ARF (Figure 2). In cell-cycle assays, the induction of INK4a and ARF decreased the proportion of S-phase cells. Additionally, re-expression of INK4a also increased the amount of apoptotic cells in induced cell lines, while re-expression of ARF did not have this effect. Since CDKN2A is a well-known cell cycle regulator, deregulation of the cell-cycle might be involved in acute transformation of chronic type ATL. In fact, deregulation of the cell-cycle pathway has been reported as a predictive indicator for the outcome in diffuse large B-cell lymphoma patients (Cancer Cell, 22:359-372). Therefore, we examined whether chronic ATL patients had alterations in cell-cycle related genes and found that chronic ATL patients could be divided into two groups. The group possessing alterations in these genes (referred to as “Cell cycle Alteration”) showed poorer prognosis compared with the group lacking such alterations (referred to as “Clean”) (p-value= 0.037) (Figure 3). Additionally, patients with such alterations tended to have earlier progression to acute type ATL. Conclusion These findings indicated that cell cycle-related genes play an important role in acute transformation and should serve as good prognostic markers for chronic type ATL. Disclosures: No relevant conflicts of interest to declare.

TEL-JAK2 transgenic mice develop T-cell leukemia

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3891-3899 ◽  
Author(s):  
Clémence Carron ◽  
Françoise Cormier ◽  
Anne Janin ◽  
Virginie Lacronique ◽  
Marco Giovannini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Fusion Gene ◽  
Lymphoid Cells ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Amino Terminal ◽  
Transgenic Progeny

We previously reported a fusion between TEL and JAK2in a t(9;12)(p24;p13) chromosomal translocation in childhood acute T-cell leukemia. This fusion gene encodes a TEL-JAK2 chimeric protein in which the 336 amino-terminal residues of TEL, including its specific self-association domain, are fused to the kinase domain of JAK2. TEL-JAK2 exhibits constitutive activation of its tyrosine kinase activity which, in turn, confers growth factor–independent proliferation to the interleukin-3–dependent Ba/F3 hematopoietic cell line. To elucidate the properties of TEL-JAK2 in primary cells and to create an animal model for TEL-JAK2–induced leukemia, we generated transgenic mice in which the TEL-JAK2 complementary DNA was placed under the transcriptional control of the EμSR enhancer/promoter. TEL-JAK2 founder mice and their transgenic progeny developed fatal leukemia at 4 to 22 weeks of age. Selective amplification of CD8-positive T cells was observed in blood, lymph nodes, thymus, spleen, and bone marrow. Expression of a tyrosine-phosphorylated TEL-JAK2 protein and activation of STAT1 and STAT5 (signal transducer and activator of transcription) were detected in leukemic tissues. TEL-JAK2 diseased mice also displayed invasion of nonhematopoietic organs, including liver, brain, lung, and kidney, by leukemic T cells. Leukemic organs of founder and transgenic progeny contained a monoclonal/oligoclonal T-cell population as analyzed by the rearrangement of the TCRβ locus. Transplantation of TEL-JAK2 leukemic cells in nude mice confirmed their invasive nature. We conclude that the TEL-JAK2 fusion is an oncogene in vivo and that its expression in lymphoid cells results in the preferential expansion of CD8-positive T cells.

scholarly journals Requirement of the human T-cell leukemia virus p12 and p30 products for infectivity of human dendritic cells and macaques but not rabbits

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3809-3817 ◽  
Author(s):  
Valerio W. Valeri ◽  
Anna Hryniewicz ◽  
Vibeke Andresen ◽  
Kathy Jones ◽  
Claudio Fenizia ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
Primate Species ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Wild Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Human Dendritic Cells

AbstractThe identification of the genes necessary for human T-cell leukemia virus (HTLV-1) persistence in humans may provide targets for therapeutic approaches. We demonstrate that ablation of the HTLV-1 genes encoding p12, p30, or the HBZ protein, does not affect viral infectivity in rabbits and in this species, only the absence of HBZ is associated with a consistent reduction in virus levels. We observed reversion of the HTLV-1 mutants to the HTLV-1 wild-type genotype in none of the inoculated rabbits. In contrast, in macaques, the absence of HBZ was associated with reversion of the mutant virus to the wild-type genotype in 3 of the 4 animals within weeks from infection. Similarly, reversion to the wild type was observed in 2 of the 4 macaque inoculated with the p30 mutant. The 4 macaques exposed to the p12 knock remained seronegative, and only 2 animals were positive at a single time point for viral DNA in tissues. Interestingly, we found that the p12 and the p30 mutants were also severely impaired in their ability to replicate in human dendritic cells. These data suggest that infection of dendritic cells may be required for the establishment and maintenance of HTLV-1 infection in primate species.

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