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J H Jansen

Publications and source records attributed to J H Jansen.

At least 19 recordsLinked to original sources
PubMed2006

Ubiquitylation in normal and malignant hematopoiesis: novel therapeutic targets.

The modification of proteins with ubiquitin is involved in the regulation of various important biological pathways. A crucial step in this process is the modification of specific substrate proteins with ubiquitin by E3 ligases. The ubiquitylation of proteins can result in altered protein function or degradation by the 26S proteasome. Various proteins playing an important role during hematopoiesis are regulated via ubiquitin modification. Recently, alterations in ubiquitylation and proteasomal degradation have been implicated in hematological cancers. Based on these findings, novel therapies that specifically target ubiquitylation or the proteasome are currently being developed. In this review, we will highlight the role of ubiquitylation in normal and malignant hematopoiesis and discuss novel therapeutical approaches that are now tested in various hematological malignancies.

Hematopoiesis↗
PubMed2005

ID1 and ID2 are retinoic acid responsive genes and induce a G0/G1 accumulation in acute promyelocytic leukemia cells.

Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA), which results in the expression of genes that induce the terminal granulocytic differentiation of the leukemic blasts. Here we report the identification of two ATRA responsive genes in APL cells, ID1 and ID2. These proteins act as antagonists of basic helix-loop-helix (bHLH) transcription factors. ATRA induced a rapid increase in ID1 and ID2, both in the APL cell line NB4 as well as in primary patient cells. In addition, a strong downregulation of E2A was observed. E2A acts as a general heterodimerization partner for many bHLH proteins that are involved in differentiation control in various tissues. The simultaneous upregulation of ID1 and ID2, and the downregulation of E2A suggest a role for bHLH proteins in the induction of differentiation of APL cells following ATRA treatment. To test the relevance of this upregulation, ID1 and ID2 were overexpressed in NB4 cells. Overexpression inhibited proliferation and induced a G0/G1 accumulation. These results indicate that ID1 and ID2 are important retinoic acid responsive genes in APL, and suggest that the inhibition of specific bHLH transcription factor complexes may play a role in the therapeutic effect of ATRA in APL.

Basic Helix-Loop-Helix Proteins↗
PubMed2005

Monitoring gastric lymphoma in peripheral blood by quantitative IgH allele-specific oligonucleotide real-time PCR and API2-MALT1 PCR.

Gastric extranodal marginal zone lymphoma (EMZL) often shows prolonged localised disease, but the present study demonstrated the presence of tumour cells in peripheral blood (PB) of low stage patients. We studied the presence of tumour cells in PB in gastric lymphoma patients harbouring or lacking t(11;18)(q21;q21), by real-time immunoglobulin (Ig)H allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) and API2-MALT1 PCR. Tumour cells were exclusively detected in PB of t(11;18)(q21;q21)+-EMZL patients. The presence of tumour cells in PB and gastric biopsy follow-up samples showed a good correlation in these patients, suggesting clinical relevance for monitoring of tumour cells in PB of gastric t(11;18)(q21;q21)+-EMZL patients.

Adult↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2004

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Apoptosis is an essential process for the selection and survival of lymphocytes. Resistance to apoptosis can promote malignant transformation of hematopoietic cells. Proteins that regulate apoptosis may therefore be critically involved in the development of hematological cancer. A delicate balance between pro- and antiapoptotic mechanisms determines whether a cell death signal can activate the execution of the apoptotic cell death program. The family of inhibitor of apoptosis (IAP) proteins is a recently identified, novel category of apoptosis-regulatory proteins. IAPs can inhibit the activation of caspases that are the executioners of apoptosis, activated by both the extrinsic and intrinsic pathway. IAPs may thereby set the threshold for apoptosis-activation and play a key role in the regulation of apoptotic cell death. IAPs themselves are also subject to strict regulation through feedback mechanisms. This paper focuses on the role of IAP family proteins in the regulation of apoptosis and discusses implications for their involvement in cancer and possible use for cancer therapy, especially in leukemias and lymphomas.

Animals↗
PubMed2002

Acquired skewing of Lyonization remains stable for a prolonged period in healthy blood donors.

The pattern of X-chromosome inactivation (XCIP), or Lyonization, can be used to distinguish monoclonal from polyclonal cell populations in females. However, a skewed XCIP exists in hematopoietic cells in approximately 40% of healthy elderly females, interfering with interpretation of clonality assays. In hematopoiesis, an active stem cell pool is assumed to be present within a larger population of inactive stem cells, with a continuous exchange of cells between the two compartments. The assumption that the active stem cell pool size decreases with age may explain the phenomenon of acquired skewing occurring by chance and predicts the XCIP of this population to fluctuate. This fluctuation should be reflected in the XCIP of peripheral granulocytes. We examined the XCIP for fluctuations in time in peripheral granulocytes, monocytes and T cells of young, middle-aged and elderly healthy females. We used an optimized HUMARA PCR assay that eliminates unbalanced DNA amplification. We found no fluctuations in XCIP in any age group in up to 18 months follow-up. We conclude that acquired skewing arises gradually in life without fluctuations in XCIP and that analysis at multiple time points cannot distinguish monoclonal hematopoiesis from normal, skewed hematopoiesis.

Adult↗
PubMed2001

Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein.

In most cases of acute promyelocytic leukemia (APL), a fusion of the promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha) genes occurs, resulting in the expression of a PML-RARalpha chimeric protein. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found fusing RARa with other genes. Four variant mutations have been described, and the t(11;17)(q21;q23) translocation generating a promyelocyte leukemia zinc finger (PLZF)-RARalpha fusion gene is the most common. PLZF-RARalpha-positive APL forms a clinically distinct group because unlike PML-RARalpha-positive leukemia, it does not respond to retinoic acid with terminal granulocytic differentiation of the cells, and remissions cannot be achieved with retinoids alone. At the molecular level, this has been explained by the retinoic acid-insensitive binding of corepressor proteins to the PLZF part of the fusion protein, leading to sustained repression of target genes that are important for cellular differentiation. Targeting of the PLZF-RARalpha-bound corepressor complexes using a combination of all-trans retinoic acid (ATRA) and deacetylase inhibitors has shown that the repression of target genes can be relieved, allowing differentiation of the cells. In addition, when a combination of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) is applied, the cells may be forced to undergo terminal differentiation, both in vitro and in vivo. This suggests that signals from the activated G-CSF receptor may induce the release of corepressor proteins from PLZF. Together, these findings indicate that PLZF-RARalpha-positive leukemia is not completely resistant to differentiation induction if the proper costimuli are given.

Antineoplastic Agents↗
PubMed2001

Degradable dU-based DNA template as a standard in real-time PCR quantitation.

Development of real-time quantitative PCR assays requires suitable positive controls. For assays with clinical applications, these controls may be difficult to obtain because some molecular aberrations are rare and patient material may be available in limited amounts. Because of the risk of introducing contaminations in the laboratory, cloned DNA is not a desirable alternative. We describe the use of dU-containing DNA as a positive control template in real-time quantitative PCR. dU-DNA constructs can be decontaminated by adding uracil N-glycosylase (UNG) to the reaction mixture. In addition, dU-DNA can be used for accurate quantification, because it allows quantification to be expressed in numbers of molecules. Since synthetic dU-DNA constructs can easily be quantitated spectroscopically, they provide a more accurate control than arbitrary cell line units. We applied this method for the detection of the E2A-Pbx1 gene fusion and show that UNG-containing reactions can be employed for diagnostics without loss of sensitivity, and that for positive and quantitative controls UNG negative reactions can be used. The use of dU-DNA provides a novel type of control template that can easily be integrated into existing PCR protocols.

DNA↗
PubMed2001

Identification of a novel CBFB-MYH11 transcript: implications for RT-PCR diagnosis.

INTRODUCTION: The chromosome rearrangements inv(16)(p13q22) or t(16;16)(p13;q22) are present in approximately 10% of all cases with de novo acute myeloid leukemia and define a subgroup with a favorable prognosis. Both aberrations result in a CBFB-MYH11 fusion gene that can be detected by RT-PCR. PATIENTS AND METHODS: To date, a total of 10 different in-frame CBFB-MYH11 fusion transcripts have been identified. A newly described transcript can not be amplified with the commonly used PCR primers since the MYH11 junction is located outside the amplified region (MYH11 cDNA position 2134). RESULTS: We describe here a robust two-step RT-PCR assay that reliably detects all known CBFB-MYH11 transcripts types, including the new variant. CONCLUSION: Because all previously established RT-PCR protocols may miss the new CBFB-MYH11 transcript, we propose to use the improved RT-PCR approach described here for the reliable detection of all known CBFB-MYH11 fusion transcripts.

Biomarkers, Tumor↗
PubMed2000

Retinoic acid receptor fusion proteins: friend or foe.

Acute promyelocytic leukemia (APL) is characterized by a block in differentiation of hematopoietic cells at the promyelocytic stage of development. This disease is uniquely sensitive to treatment with pharmacological doses of all-trans retinoic acid (ATRA), and the combination of ATRA with chemotherapy has improved the durable disease-free survival in these patients to up to 80%. APL is characterized by chromosomal translocations that lead to the fusion of the retinoic acid receptor-alpha (RARalpha) to various partner genes. RARalpha functions as a ligand-inducible transcription factor and the aberrant RARalpha fusion proteins contribute to leukemic transformation by dominant inhibition of the expression of target genes that are important for cellular differentiation. This may at least in part be explained by an abnormally strong interaction with corepressor proteins leading to deacetylation of DNA and silencing of target genes. Most RARalpha fusion proteins can still be induced to transactivate genes, but only at very high doses of ligand, explaining why pharmacological doses of ATRA are necessary to obtain a therapeutic effect in these patients.

Hematopoiesis↗
PubMed2000

Molecular remission of Philadelphia/bcr-abl-positive acute myeloid leukaemia after treatment with anti-CD33 calicheamicin conjugate (gemtuzumab ozogamicin, CMA-676).

The anti-CD33 monoclonal antibody linked to NAc-gamma calicheamicin gemtuzumab ozogamicin (CMA-676) was used to treat a patient with Philadelphia/bcr-abl-positive acute myeloid leukaemia. We report a morphological and cytogenetic complete remission after treatment with two doses of gemtuzumab ozogamicin as a single agent. Using real-time polymerase chain reaction (PCR), gemtuzumab ozogamicin treatment resulted in a 3-log tumour mass reduction in bone marrow.

Acute Disease↗
PubMed1999

Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor.

The combined use of retinoic acid and chemotherapy has led to an important improvement of cure rates in acute promyelocytic leukemia. Retinoic acid forces terminal maturation of the malignant cells and this application represents the first generally accepted differentiation-based therapy in leukemia. Unfortunately, similar approaches have failed in other types of hematological malignancies suggesting that the applicability is limited to this specific subgroup of patients. This has been endorsed by the notorious lack of response in acute promyelocytic leukemia bearing the variant t(11;17) translocation. Based on the reported synergistic effects of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF), we studied maturation of t(11;17) positive leukemia cells using several combinations of retinoic acid and growth factors. In cultures with retinoic acid or G-CSF the leukemic cells did not differentiate into mature granulocytes, but striking granulocytic differentiation occurred with the combination of both agents. At relapse, the patient was treated with retinoic acid and G-CSF before reinduction chemotherapy. With retinoic acid and G-CSF treatment alone, complete granulocytic maturation of the leukemic cells occurred in vivo, followed by a complete cytogenetical and hematological remission. Bone marrow and blood became negative in fluorescense in situ hybridization analysis and semi-quantitative polymerase chain reaction showed a profound reduction of promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion transcripts. This shows that t(11;17) positive leukemia cells are not intrinsically resistant to retinoic acid, provided that the proper costimulus is administered. These observations may encourage the investigation of combinations of all-trans retinoic acid and hematopoietic growth factors in other types of leukemia.

Adult↗
PubMed1999

Dexamethasone does not counteract the response of acute promyelocytic leukaemia cells to all-trans retinoic acid.

Retinoic acid syndrome is a serious condition that may complicate the treatment of acute promyelocytic leukaemia patients. This syndrome may be treated effectively with high-dose corticosteroid therapy and, as a result, many patients with acute promyelocytic leukaemia receive dexamethasone at some point during treatment. We investigated whether dexamethasone would also antagonize the beneficial effects of retinoic acid. In t(15;17)-positive NB4 cells, dexamethasone did not affect the retinoic acid induced differentiation, normalization of PML-nuclear bodies or the induction of thrombomodulin mRNA. Finally, dexamethasone did not inhibit the anti-proliferative effect of retinoic acid but rather showed anti-proliferative activity itself.

Antineoplastic Agents, Hormonal↗
PubMed1999

TRIADs: a new class of proteins with a novel cysteine-rich signature.

Triad1 was recently identified as a nuclear RING finger protein, which is up-regulated during retinoic acid induced granulocytic differentiation of acute leukemia cells. Here we show that a cysteine-rich domain (C6HC), present in Triad1, is conserved in at least 24 proteins encoded by various eukaryotes. The C6HC consensus pattern C-x(4)-C-x(14-30)-C-x(1-4)-C-x(4)-C-x(2)-C-x(4)-H-x(4)-C defines this structure as the fourth family member of the zinc-binding RING, LIM, and LAP/PHD fingers. Strikingly, in 22 of 24 proteins the C6HC domain is flanked by two RING finger structures. We have termed the novel C6HC motif DRIL (double RING finger linked). The strong conservation of the larger tripartite TRIAD (two RING fingers and DRIL) structure indicates that the three subdomains are functionally linked and identifies a novel class of proteins.

Amino Acid Sequence↗
PubMed1998

The judgement of facial expressions by depressed patients, their partners and controls.

BACKGROUND: Research has shown that cognitive and interpersonal processes play significant roles in depression development and maintenance. Depressed patients judgments of emotions displayed in facial expressions, as well as those of their partners, allow for better understanding of these processes. METHODS: In this study, twenty major depression outpatients, their partners and control persons (matched on the sex and age of the partner) judged facial expressions as to the emotions they felt were portrayed, at the patients outpatient admission. It was expected that the patients would judge the facial expression more negatively and less positively than their partners and that the partners would judge more negatively and less positively than the controls. RESULTS: It was found that while both the patients and partners judged less positive emotions than the controls, the patients and partners did not judge the expressions differently. A trend in the same direction was found between the three groups as to judgment of negative emotions. CONCLUSION: These findings are related back to interpersonal and cognitive theories of depression. LIMITATION: A limitation of this study was the somewhat small patient population available for study. CLINICAL RELEVANCE: This study helps to shed light on the similarity between interpersonal and cognitive processes of depressed patients and their partners.

Adult↗
PubMed1998

In situ complement activation in porcine membranoproliferative glomerulonephritis type II.

Pigs genetically deficient in complement factor H all develop lethal membranoproliferative glomerulonephritis (MPGN) type II characterized by massive glomerular deposits of complement, intramembranous dense deposits, and mesangial hypercellularity. To elucidate the chronological relationship between these glomerular changes, and to precisely determine the localization of glomerular complement deposits, we studied kidney specimens from factor H-deficient piglets at different ages from fetal life until terminal kidney failure had developed. Deposits of C3 and the terminal complement complex localized within the glomerular basement membrane (GBM) were present already in factor H-deficient fetuses, without concurrent intramembranous dense deposits or mesangial hypercellularity. Incipient subendothelial dense deposits containing complement appeared no earlier than four days after birth, and intramembranous dense deposits in older piglets with established MPGN type II also contained large amounts of complement as detected by immune electron microscopy. Onset of kidney failure coincided with pronounced mesangial hypercellularity and expansion, compromising glomerular capillary patency. Formation of glomerular capillary wall double contours coincided with electron microscopic evidence of laminar disintegration of intramembranous dense deposits. Complement was also deposited in the mesangial matrix, but not on glomerular cells. We conclude that all components of the alternative and terminal pathways of complement have access into the GBM and the mesangial matrix. In the absence of factor H, complement is spontaneously activated and deposited in situ in these locations resulting in dense deposit formation. It is proposed that factor H dysfunction may play an essential role even in human MPGN type II.

Animals↗