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Results for “Gene Expression Regulation, Leukemic”

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PubMed1996

Induction of OX40, a receptor of gp34, on T cells by trans-acting transcriptional activator, Tax, of human T-cell leukemia virus type I.

gp34, which we had identified as a target molecule of the trans-activation by Tax of human T-cell leukemia virus type I (HTLV-I), has been found to bind OX40, a member of the tumor necrosis factor receptor family, resulting in growth stimulation of activated T cells. We here demonstrate that not only gp34 (OX40L), but also OX40 can be transcriptionally activated by Tax. Three Tax-producing human T-cell lines carrying the HTLV-I genome expressed OX40 on their surfaces. Furthermore, Tax-induced transcriptional activation of OX40 was shown in Tax-inducible JPX-9 cells. These results demonstrate that both OX40 and its ligand (gp34) are constitutively expressed on the surfaces of Tax-expressing T lymphocytes, suggesting that the OX40L/OX40 system contributes to growth stimulation of the virus-infected T cells.

Cadmium↗
PubMed1996

HLA-G transcription studies during the different stages of normal and malignant hematopoiesis.

Specific expression of the non classical class I HLA-G gene on trophoblasts, the only fetal tissue in contact with maternal cells which lack MHC class I antigens, may indicate a role of this gene in fetal-maternal tolerance. We recently reported HLA-G transcription in peripheral blood leukocytes. In this work, we have investigated HLA-G transcription in hematopoietic stem cells, in different hematopoietic lineages and in malignant cells by using a RT-PCR technique. PCR amplification with primers specific to the exon 2 and the 3' untranslated region has enabled to detect HLA-G transcription in B and T cell populations. No transcription was found in CD34+ cells, in thymocytes, in polynuclear cells, in monocytes and in natural killer cells. Among the malignancies analyzed, HLA-G is transcribed in 2 of 13 cases of acute leukemia characterized by a monocytic contingent, in 3 of 6 CLL and in all the cases of B-NHL (n = 6). No HLA-G transcription was detected in myeloma (n = 2). The splicing type does not seem to be linked to a lymphocyte subpopulation nor to a malignant proliferation stage. These results suggest that HLA-G is a marker of mature lymphoid cells and may play an immunological function as a peptide presenting molecule. HLA-G transcription in some cases of malignancy might indicate a contribution to the tumoral progression by blocking natural killing reaction.

Antigens, Neoplasm↗
PubMed1995

Different clonal origin of B-cell populations of chronic lymphocytic leukemia and large-cell lymphoma in Richter's syndrome.

Richter's syndrome is defined as the morphologic transformation of chronic lymphocytic leukemia (CLL) into diffuse large-cell lymphoma (DLL). To determine the clonal nature of the two malignancies, we microdissected the CLL and DLL cells from a lymph node of Richter's syndrome and analyzed the sequences of the rearranged Ig VH-D-JH genes of the two lymphomas. Using the Ig VH-D-JH sequence as a marker of clonality, we delineated the clonal relationship of the CLL and DLL cells. The microdissected CLL and DLL cells productively rearranged different VH, D, and JH genes, suggesting that these DLL B cells emerge as discrete elements independent of the CLL B-cell population. The productively rearranged Ig V gene sequence of the CLL clone was 100% identical to the VH6 germline gene, but the rearranged Ig VH gene of the DLL clone was somatically point-mutated based on comparison of its sequence with those of reported germline genes. In the DLL clone, the random distribution and nature of the somatic point-mutations suggests a lack of antigen selection; the identity of the somatic point-mutations in multiple independent isolates of the same B-cell clone suggests a lack of intraclonal diversity. Thus, Richter's syndrome DLL B cells are monoclonal and can emerge as discrete elements independent of the preexisting CLL cells; antigen selection and clonal diversification are not necessarily associated with the events leading to this aggressive neoplastic transformation.

Aged↗
PubMed1989

Molecular mechanisms of regulation of HTLV-1 gene expression and its association with leukemogenesis.

Human T-cell leukemia virus type 1 (HTLV-1) has two trans-acting regulator genes, tax and rex, in the pX region. The tax gene is a trans-acting transcriptional activator of the long terminal repeat (LTR) and also of the cellular gene for IL-2R alpha. The latter seems to explain initiation of abnormal growth of HTLV-1 infected cells. The rex gene is a posttranscriptional regulator accumulating gag and env mRNA and also indirectly suppressing the transcription. The regulation requires two cis-acting elements, the LTR sequence at the 3' terminus and 5' splice signal, suggesting a novel mechanism of RNA processing in the nucleus. These two trans-activator genes are essential for efficient replication of HTLV-1 and also explain its poor replication competence and tendency to be latent in vivo.

Animals↗
PubMed2002

The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines.

The novel prodrug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on hematopoietic malignancies. In this study, we show that 21 primary samples of acute leukemia were sensitive to the antiproliferative effects of AN-9, with a 50% inhibitory concentration (IC(50)) of 45.8 +/- 4.1 microM. In colony-forming assays, primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold more sensitive to AN-9 than the normal hematopoietic progenitors, erythroid burst-forming units and granulocyte/monocyte colony-forming units. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemoresistance, which is often typical of relapsed cancers. Remarkably, a T-ALL sample at diagnosis and an acute myeloid leukemia sample at relapse that were resistant to doxorubicin in vitro were sensitive to AN-9, with an IC(50) of 50 microM for both samples. More strikingly, samples from 2 infants with t(4;11) ALL obtained at diagnosis and relapse each were the most sensitive to AN-9, with IC(50) values of 25 microM and 17 microM, respectively. Furthermore, a doxorubicin-resistant clone of HL60, HL60/ADR, obtained by the transfection of the MDR-1 gene, was equally sensitive to AN-9 cytotoxicity as the parental cells. AN-9 induced the expression of p21 in an infant leukemia sample with 11q23 rearrangement, but not in T- or B-precursor ALL. Collectively, our results suggest that AN-9 is a selective agent for hematopoietic malignancies that can circumvent the mechanisms of chemoresistance limiting most conventional chemotherapy.

Acetylation↗
PubMed2005

NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo.

Activated NF-kappaB is a critical mechanism by which lymphoma cells infected by Epstein-Barr virus (EBV/HHV-4) and Kaposi sarcoma herpesvirus (KSHV/HHV-8) are protected from apoptotic stress. Selective pharmacologic inhibition of constitutive NF-kappaB activity induces apoptosis in KSHV- and EBV-infected lymphoma cells. In both tumor types, pharmacologic inhibition of NF-kappaB in vitro induced identical mitochondrially mediated apoptosis cascades. Assessment of gene regulation by microarray analysis revealed that the inhibition of NF-kappaB in tumor cells results in the down-regulation of a distinct group of prosurvival genes, including cIAP-1, cIAP-2, cFLIP, and IL-6. Using EBV- and KSHV-associated lymphomas in a murine system, we demonstrated that Bay 11-7082, a selective pharmacologic inhibitor of NF-kappaB, prevents or delays tumor growth and prolongs disease-free survival. Inhibition of NF-kappaB activity and tumor growth responses were further documented using a traceable reporter KSHV-positive cell line and in vivo imaging. These findings indicate that specific NF-kappaB-regulated survival factors work cooperatively to protect KSHV- and EBV-infected lymphoma cells from apoptosis such that they promote the establishment and progression of KSHV- and EBV-associated lymphomas in mice. They also support the use of selective NF-kappaB inhibitors in the treatment of herpesvirus-associated lymphomas.

Animals↗
PubMed2005

TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia.

PURPOSE: Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease for which natural history can be predicted based on the presence or absence of immunoglobulin (Ig) variable heavy chain (V(H)) gene mutations. Herein we report selective epigenetic silencing of the transcription factor TWIST2 (DERMO1) in Ig V(H) mutated CLL and describe a semiquantitative assay to study promoter methylation of this gene in primary tumor cells. MATERIALS AND METHODS: TWIST2 promoter methylation was identified by restriction landmark genome scanning. Southern blot (SB), bisulfite sequencing, and combined bisulfite restriction analysis (COBRA), and quantitative SB-COBRA was performed to study methylation of the TWIST2 promoter. Reverse transcription polymerase chain reaction assays were used to study TWIST2 expression in CLL cells. RESULTS: Following identification and confirmation of TWIST2 methylation in CLL patients, we demonstrated that expression of this transcription factor is related to the degree of promoter methylation. Expression of TWIST2 in a CLL cell line in which the promoter is methylated was increased following decitabine treatment. We next studied 53 patients by COBRA and demonstrated that 72% of patient samples with mutated Ig V(H) show TWIST2 methylation, while only 16% of patient samples with unmutated Ig V(H) were methylated (P < .001). In a subset of patients, methylation of TWIST2 correlated with mRNA expression. CONCLUSION: TWIST2 is differentially methylated in CLL cells relative to Ig V(H) mutational status and can be quantitatively monitored by SB-COBRA. Based on the known role of TWIST2 in silencing p53 function in other malignancies, future studies should focus on the role of TWIST2 in CLL and related lymphoproliferative diseases.

Antimetabolites, Antineoplastic↗
PubMed2000

Divergent expression of cyclin-dependent kinase inhibitors (CKI) and p14ARF/p16 beta in non-Hodgkin's lymphomas and chronic lymphocytic leukemia.

Chronic B-cell lymphocytic leukaemia (CLL) and low-grade B-cell Non Hodgkin's lymphomas (Lg-NHL) are characterized by slow accumulation of neoplastic cells arrested in the G0/G1 phase of the cell cycle. In contrast, proliferation rates are high in aggressive B-cell lymphomas (Hg-NHL). Divergent expression of cyclin-dependent kinase inhibitors (CKI) in the cell cycle may contribute to these differences. We analysed CLL as well as low and high grade B-cell NHL for expression of G1-specific and universal CKI by competitive RT-PCR and immunostaining. p16(INK4A) expression was low in all types of neoplasms. Highest p14(ARF) /p16 beta expression levels were found in normal lymphocytes. Expression of this CKI was significantly lower in CLL, but still higher in CLL than in the lymphomas (median 27 vs. 3 mRNA transcripts x 10(3), p = 0.0001). p14(ARF) /p16 beta immunostaining correlated with mRNA expression. Highest p21 mRNA levels were found in CLL, but three of four CLL with abundant p21 mRNA production were negative on immunostaining. High grade lymphomas showed markedly decreased p21 expression (3.9 in Hg-NHL vs. 12 in Lg-NHL and 29 in CLL; values expressed as mRNA transcripts x 10(3), p < 0.009). mRNA and protein expression of p27 was considerably higher in CLL than in the lymphomas. Differential CKI expression in various B-cell neoplasias may provide important biological markers, if not the molecular underpinning of their different cell cycle kinetics. Targeted interference with such genes governing cell cycle control in lymphoid neoplasia may pave the way towards new treatment strategies.

Adult↗
PubMed1993

Expression of human endogenous retrovirus (HERV-K) in chronic myeloid leukemia.

We have previously demonstrated the presence of a reverse transcriptase-like enzyme in retroviral particles from patients with essential thrombocythemia, polycythemia vera, and chronic myelogenous leukemia. It was subsequently shown that the human genome contains 50 copies of HERV-K. HERV-K is a human endogenous class I retroviral element that contains gag, pol, and env open reading frames. Using both reverse transcriptase-polymerase chain reaction and ribonuclease protection assays, it is demonstrated that the HERV-K pol is expressed in human blood leukocytes. The data indicates that this expression is restricted in CML white cells and is the result of gene regulation.

Amino Acid Sequence↗
PubMed1995

Differential usage of an autoantibody-associated VH gene, VH4-21, by human B-cell tumors.

Selection of immunoglobulin variable region genes for recombination in B cells takes place from among those VH and VL gene segments available in the unrearranged germ line repertoire. In the case of neoplastic B cells, there is apparent deviation in the use of V-genes from that expected on a random basis, both for VH and for VL. Also, the preferred V-genes, and their patterns of mutation, differ among the various categories of B-cell tumor possibly reflecting the distinct origins and clonal histories on the individual tumor cells. This review focuses on a single VH gene, VH4-21, which is a member of the VH4 family, and which appears selectively to encode immunoglobulins with autoantibody activity, particularly anti-red cell antibodies. The pattern of usage of this VH gene by B-cell tumors demonstrates clear asymmetry among different tumor types. Also, the mutations detected in this relatively non-polymorphic gene indicate that antigen, possibly autoantigen, may influence the behavior of the tumor cell.

Agglutinins↗
PubMed1996

Overexpression of the MDM2 oncogene in leukemia and lymphoma.

A cellular phosphoprotein that binds to and inactivates p53 has recently been identified as a product of the oncogene MDM2. Amplification of the MDM2 gene was found in more than a third of sarcomas and in a subset of malignant gliomas. Despite the absence of amplification, the MDM2 gene was overexpressed in some types of leukemias and lymphomas. Overexpression was significantly more frequent in the low-grade type of B-cell non-Hodgkin's lymphoma (B-NHL) than in the intermediate/high grade types of lymphoma and the overexpression was also significantly more frequent in the advanced rather than the earlier stages of B-cell chronic lymphocytic leukemia (B-CLL) and B-NHL. This suggests that MDM2 could play a role, via the p53 pathway, in tumorigenicity and/or in disease progression in some hematological malignancies. However, in the light of our findings that, in a few cases, both the overexpression of MDM2 and mutant-type p53 was seen, it is possible that MDM2 overexpression may also promote neoplastic growth by mechanisms other than inactivation of the p53 protein.

Animals↗
PubMed2000

Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-kappa B activation.

Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator protein Tax plays a critical role in HTLV-I-induced transformation and apoptosis resistance by inducing I kappa B-alpha degradation, resulting in the activation of the NF-kappa Bpathway. In these HTLV-I-transformed cells, arsenic trioxide (As) and interferon (IFN)-alpha synergize to induce cell cycle arrest and apoptosis. We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bax, or p53 expression. However, combined As and IFN induce the degradation of Tax, associated with an up-regulation of I kappa B-alpha resulting in a sharp decrease in RelA DNA binding nuclear factor (NF)-kappa B complexes because of the cytoplasmic retention of RelA. Taken the role of Tax in HTLV-I-induced transformation, its down-regulation probably accounts for cell death induction through inactivation of the NF-kappa B pathway. Such specific targeting of the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-alpha in acute promyelocytic leukemia, provides strong rational for combined As-IFN therapy in ATL patients. (Blood. 2000;96:2849-2855)

Apoptosis↗
PubMed2003

Statistical modeling and visualization of molecular profiles in cancer.

Current cancer classifications using morphological criteria produce heterogeneous classes with variable prognosis and clinical course. By measuring gene expression for thousands of genes in a single hybridization experiment, microarrays have the potential to contribute to more effective classifications based on molecular information. This gives hope to improve both prognosis and treatment. Statistical methods for molecular classification have focused on using high dimensional representations of molecular profiles to identify subclasses. These can be noisy, unstable, and highly platform-specific. In this article, we emphasize the notion of molecular profiles based on latent categories signifying under-, over-, and baseline expression. Following this approach, we can generate results that are more easily interpretable, more easily translated into clinical tools, more robust to noise, and less platform-dependent. We illustrate both the methods and the associated software for molecular class discovery on a data set of 244 microarrays comprising six known leukemia classes.

Child↗
PubMed2003

The role of breast cancer resistance protein in acute lymphoblastic leukemia.

PURPOSE: Overexpression of the transporter ABCG2, also known as breast cancer resistance protein and mitoxantrone resistance protein, can confer resistance to a variety of cytostatic drugs, such as mitoxantrone, topotecan, doxorubicin, and daunorubicin. This study analyzes the ABCG2 expression and activity in 46 human de novo acute lymphoblastic leukemia B- and T-lineage (ALL) samples. EXPERIMENTAL DESIGN: ABCG2 expression was measured flow cytometrically with the BXP-34 monoclonal antibody. ABCG2 functional activity was determined flow cytometrically by measuring mitoxantrone accumulation in combination with the ABCG2 inhibitor fumitremorgin C (FTC). To determine a possible effect of the transporters P-glycoprotein and multidrug resistance-associated protein (MRP1 and MRP2) on mitoxantrone accumulation, the accumulation was investigated in the presence of the P-glycoprotein inhibitor PSC 833 and MRP inhibitor MK-571. The ABCG2 gene was sequenced to investigate the amino acid at position 482. RESULTS: In B-lineage ALL (n = 23), the median BXP-34:IgG1 ratio was higher, namely 2.4 (range, 1.7-3.7), than in T-lineage ALL (n = 23; 1.9; range, 1.2-6.6; P = 0.003). The addition of FTC to mitoxantrone treatment caused a median increase in mitoxantrone accumulation of 21% (range, 0-140%) in B-lineage ALL. In T-lineage ALL, this FTC effect was less pronounced (5%; range, 0-256%; P = 0.013). The influence of FTC on mitoxantrone accumulation correlated with ABCG2 protein expression (r = 0.52; P < 0.001; n = 43). The increase in mitoxantrone accumulation, when FTC was added to cells treated with both PSC 833 and MK-571, correlated with the ABCG2 expression in B-lineage ALL but not in T-lineage ALL. Sequencing the ABCG2 gene revealed no ABCG2 mutation at position 482 in patients who accumulated more rhodamine after FTC. CONCLUSIONS: This study shows that ABCG2 is expressed higher and functionally more active in B-lineage than in T-lineage ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Cell cycle analysis of p26-BCL-2 protein levels in proliferating lymphoma and leukemia cell lines.

The BCL-2 (B-cell lymphoma/leukemia-2) gene is frequently involved in t(14;18) translocations in non-Hodgkin's lymphomas and encodes a 26-kDa intracellular, membrane-associated protein. Expression of the BCL-2 gene has previously been correlated with cellular proliferation in normal and neoplastic lymphoid cells under a variety of experimental conditions. To examine the regulation of p26-BCL-2 protein levels during the cell cycle, we utilized the method of counterflow centrifugal elutriation to enrich for cells in various phases of the cell cycle. Relative levels of p26-BCL-2 protein were measured by immunoblotting, and comparisons were made with a cell cycle-regulated protein, p62-CYCLIN-A, and a protein whose levels are constant throughout the cell cycle, p36-PCNA (DNA polymerase-delta auxiliary factor). Relative levels of p26-BCL-2 and p36-PCNA did not vary among cell fractions enriched for specific phases of the cell cycle, whereas p62-CYCLIN-A was elevated in late S- and G2/M-phase cells. Similar results were obtained with lymphoma and leukemia cell lines that have either normal or translocated BCL-2 genes. These results obtained by elutriation were confirmed by pharmacologically inducing cell cycle arrest in proliferating lymphoid cell lines with hydroxyurea, quercetin, and nocodazole which blocked cells at S, G2, and M phases, respectively. Taken together, the data indicate that p26-BCL-2 is not a true cell cycle-regulated protein, although its levels can fluctuate in connection with changes in rates of cellular proliferation under some circumstances.

Cell Cycle↗
PubMed1992

Restricted oncogenicity of BCR/ABL p190 in transgenic mice.

A chimeric BCR/ABL oncogene encoding the p190 protein has been introduced into the mouse germline using microinjection of one-cell fertilized eggs. Founder and progeny transgenic animals, when becoming ill, were found to develop lymphoblastic leukemia/lymphoma which was transplantable to compatible recipients. Lymphoblasts were arrested at the pre-B stage of development. Expression of BCR/ABL was not detected in peripheral blood during the early stages of leukemia but became evident as the disease progressed. However, the transgene was expressed early in development in bone marrow and was also transcribed in nonhematopoietic tissues although this did not result in tumorigenesis. These results strongly suggest that the oncogenicity of BCR/ABL is limited to hematopoietic cells, including pre-B cells or their progenitors.

Animals↗
PubMed1990

[Cytologic molecular detection of oncogene expression: possibilities and prospects in hemato-oncology].

Proto-oncogenes, the normal equivalents to the transforming genes of mammalian tumorigenic retroviruses, are implicated in essential biological processes of normal human cells, like differentiation and proliferation. In vivo and in vitro studies clearly demonstrate that activation of proto-oncogenes with subsequent transformation in tumorigenic oncogenes plays an important role in induction and acceleration of the malignant disease, and also determines metastatic spread and development of resistance to chemotherapy in certain neoplasias. Investigation of these genes and analysis of their activation state should routinely be introduced in staging of hematological neoplasias, thus contributing to refinement of histopathological classification, clearer discrimination between reactive and neoplastic conditions and understanding of pathophysiological processes. Furthermore, impact on definition of high risk patients and novel therapeutic concepts based on a better definition of tumour biology may be expected from these studies. "Molecular cytology" combines detection of oncogenetic mRNA and the relevant oncoprotein on the single cell level by using "mRNA-in situ hybridization" and immuno-histochemistry. Application of this technique will allow to determine the mechanisms regulating the expression of oncogenes to define functional heterogeneity of tumour cell subsets and to clarify the relevance of minimal residual disease.

Cell Transformation, Neoplastic↗