J.H. Jansen

Preferential expression of a high number of ATP binding cassette transporters in both normal and leukemic CD34+CD38- cells.

Preferential expression of a high number of ATP binding cassette transporters in both normal and leukemic CD34+CD38− cells

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.

Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome

In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.

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.

The contextual benchmark method: benchmarking e-government services

This paper offers a new method for benchmarking e-Government services. Government organizations no longer doubt the need to deliver their services on line. Instead, the question that is more relevant is how well the electronic services offered by a particular organization perform in comparison with those offered by others. Benchmarking is currently a popular means of answering that question. The benchmarking of e-Government services has reached a critical stage where, as we argue, simply measuring the number of electronic services is not enough and a more sophisticated approach is needed. This paper details the development of a Contextual Benchmark Method (CBM). The value of CBM is that it is both benchmark- and context-driven.

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.

Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs

Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs

Genetic defects in PRC2 components other than EZH2 are not common in myeloid malignancies

To the editor: Several genetic alterations affecting loci encoding epigenetic regulators have been discovered in myeloid malignancies in the last few years. Previously, we and others identified novel mutations in the histone methyltransferase gene EZH2 .[1][1][][2]–[3][3] EZH2 encodes the

Dynamics in chimerism of T cells and dendritic cells in relapsed CML patients and the influence on the induction of alloreactivity following donor lymphocyte infusion

Donor lymphocyte infusion (DLI) after allogeneic SCT induces complete remissions in approximately 80% of patients with relapsed CML in chronic phase, but some patients do not respond to DLI. We studied absolute numbers of dendritic cell (DC) subsets and chimerism in T cells and two subsets of blood DCs (myeloid DCs (MDCs) and plasmacytoid DCs (PDCs)) in relation to DLI-induced alloreactivity. Based on T cell and DC chimerism, we identified three groups. Four patients were completely donor chimeric in T cells and DC subsets. These patients had an early stage of relapse, and three of the four patients attained complete molecular remission (CMolR) without significant GVHD. Six patients were completely donor in T cells and mixed chimeric in DC subsets. All patients entered CMolR, but this was associated with GVHD in four and cytopenia in three patients. Five patients had mixed chimerism in T cells and complete recipient chimerism in MDC; only two patients entered CMolR. Our data suggest that the combination of donor T cells and mixed chimerism in DC subsets induces a potent graft-versus-leukemia (GVL) effect in association with GVHD. DLI in patients with an early relapse and donor chimerism in both T cells and DC subsets results in GVL reactivity without GVHD.

Channel choice and source choice of entrepreneurs in a public organizational context: the dutch case

Most e-Government research focuses on citizens, the use and effects of electronic channels and services. However, businesses are an important target group for governmental agencies as well. Governmental agencies have a duty to inform businesses and to make this information easy to access. In order to increase accessibility it is important to closely relate to the behavior of users. Therefore, the purpose of the present investigation is to gain insight about the channel and source choice of entrepreneurs in a public organizational context. According to 323 entrepreneurs, who filled out an electronic questionnaire, the internet is the most preferred channel and a search engine is the most preferred source for obtaining governmental information. Business-, entrepreneur-and situational characteristics have, although small, effect on these choices.