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M Lübbert

Publications and source records attributed to M Lübbert.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of five prognostic scoring systems, the French-American-British (FAB) and World Health Organization (WHO) classifications in patients with myelodysplastic syndromes: Results of a single-center analysis.

We retrospectively studied 89 consecutive patients diagnosed with primary myelodysplastic syndrome (MDS) over a period of 10 years to (1) identify prognostic factors for overall survival (OS) and leukemia-free survival (LFS); (2) to assess and compare the Bournemouth-, Spanish-, Düsseldorf-, Lille-, and the International prognostic scoring systems (IPSS); and to (3) compare the French-American-British (FAB) and World Health Organization (WHO) classifications. The median age of patients was 63 years (range, 26-85). Karyotype analyses were done in 85 patients (96%). Median OS was 3 years; 67 patients (75%) have died, and 28 (31%) had progression to acute myeloid leukemia (AML). Major independent prognostic variables for both OS and LFS (multivariate analysis) were percentage of bone marrow (BM) blasts (P < 0.0001), and in patients with cytogenetic data available, cytogenetic risk groups by Lille-score (OS, P = 0.031/LFS, P = 0.002) and IPSS (OS, P = 0.024). All five prognostic scoring systems successfully discriminated risk groups as regards OS and LFS, but in patients with cytogenetic data available, the major independent prognostic score for OS (P < 0.0001) and LFS (P = 0.006) was the IPSS. The FAB and WHO classifications also successfully discriminated between risk groups. The new WHO subgroups [refractory cytopenia with multilineage dysplasia (RCMD), with (RCMD-RS) or without ringed sideroblasts] showed a significantly (P = 0.0454) different prognosis for OS, but not for LFS (P = 0.0839), in comparison to the subgroups having erythroid dysplasia only (RA/RARS). Risk stratification into refractory anemia with excess blast-I (RAEB-I) and RAEB-II tended to yield different prognoses for OS and LFS. The 5q-minus syndrome strongly predicted for a good prognosis. In patients treated with the demethylating agent decitabine (n = 24), IPSS "poor risk" cytogenetics were unable to predict for the expected worse prognosis when compared to "intermediate-risk" cytogenetics. In conclusion, we confirm in a single-center patient cohort that the use of the WHO classification improves the predictive value of the FAB classification and that, in patients with cytogenetic data available, the IPSS can be used for clinical decision-making.

Adult↗
PubMed2006

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO.

A 117 bp fragment of the human ELA2 promoter has been characterized that can act as a minimal promoter for the expression of neutrophil elastase. Chromatin immunoprecipitation and siRNAs revealed that expression of ELA2 is regulated by the acute myeloid human leukemia 1 protein (AML1), C/EBPalpha, PU.1 and c-Myb transcription factors. ELA2 has also been investigated as a possible target of the leukemic fusion protein AML1-ETO resulting from the t(8;21) chromosomal translocation. AML1-ETO, like AML1, binds the ELA2 promoter in the myeloid cell lines Kasumi-1 and U937, but unexpectedly fails to significantly alter expression of ELA2. Although AML1-ETO downregulates the expression of C/EBPalpha, changes in C/EBPalpha expression do not correlate with changes in the expression of ELA2. Our observations indicate that AML1-ETO may not be a constitutive repressor of gene expression in every case in which it can associate with DNA, either on its own or in conjunction with C/EBPalpha. Since neither ETO nor AML1-ETO are typically expressed in hematopoietic progenitors, we hypothesize that it is the interactions between AML1-ETO and regulatory cofactors in disease-state cells that alter gene expression programs during hematopoiesis. These protein-protein interactions may not require simultaneous DNA binding by AML1-ETO for the deleterious effects of the fusion protein to be realized.

Acute Disease↗
PubMed2006

Trisomy 19 as the sole chromosomal abnormality in proliferative chronic myelomonocytic leukemia.

Distinct morphologic and clinical features associated with specific chromosomal abnormalities have been described in subgroups of myelodysplastic syndromes (MDS), which often are losses or gains and only rarely translocations. Among 103 consecutive MDS patients diagnosed and karyotyped at the Albert-Ludwigs University of Freiburg (ALU) between 1993 and 1999, two chronic myelomonocytic leukemias (CMMoL) displayed trisomy 19 (+19) as the sole chromosomal abnormality. Three further CMMoL cases with +19 as the single abnormality, two of which previously reported, were collected from other centers. Four of the five patients presented with leukocytosis and splenomegaly, and an increased number of ringed sideroblasts was observed in two cases. Treatment was low-dose Decitabine (cases 1 and 2), oral steroids (case 3), hydroxyurea (case 4), and daunorubicin/Ara-C (case 5). Transformation to acute myeloid leukemias (AML) occurred in three/five patients (cases 1, 2, and 4) 26, 12, and 22 months after diagnosis of CMMoL, respectively. We conclude that +19 as the sole anomaly is a rare but recurrent change in CMMoL, in particular of the proliferative type. It is at present unclear which gene(s) located on chromosome 19 might have a functional role for the development of this phenotype.

Aged↗
PubMed2006

Effects of 5-aza-2'-deoxycytidine on proliferation, differentiation and p15/INK4b regulation of human hematopoietic progenitor cells.

The demethylating agents 5-azacytidine and 5-aza-2'-deoxycytidine (DAC) have been shown to induce differentiation and inhibit growth of leukemic myeloid cells at low concentrations. However, the effect of DAC in changing the differentiation and proliferation behavior of normal human myeloid progenitors has rarely been investigated. Therefore, we established an in vitro model of normal hematopoietic differentiation, using CD34+ cells from mobilized peripheral blood, to study proliferation and colony formation, expression of several myeloid maturation markers and of the inhibitor of cyclin-dependent kinases p15/INK4b. Upon DAC treatment, cell growth was significantly decreased in a dose-dependent manner, without an increase in cytotoxicity. DAC treatment also resulted in a substantial increase of lysozyme-positive cells, which could be enhanced by G-CSF, a modest increase of myeloperoxidase+ and CD15+ cells, as well as an increase of colony-forming cells (CFU-GM) compared to control cells. p15/INK4b protein expression was strongly upregulated upon myeloid maturation, and additional DAC treatment did not change p15 expression or the methylation status of the p15 promoter at the noncytotoxic concentrations used. Taken together, these data indicate a role of DAC in changing myeloid progenitor cell expansion and differentiation. This model appears suitable also for global analyses of multiple differentially methylated genes.

Antigens, CD34↗
PubMed2006

Inducible expression of AML1-ETO fusion protein endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis.

AML1-ETO, a leukemia-associated fusion protein generated by the frequently occurred chromosome translocation t(8;21) in acute myeloid leukemia, was shown to exert dichotomous functions in leukemic cells, that is, growth arrest versus differentiation block. By the analysis of oligonucleotide microarray, AML1-ETO was shown to modulate the expressions of an impressive array of pro- and anti-apoptotic genes. Here, we investigate potential effects of the ecdysone inducible AML1-ETO expression on apoptosis of leukemic U937 cell line. We show that AML1-ETO significantly stabilizes death receptor Fas protein and increases proapoptotic Bak in addition to reducing Bcl-2 expression. Accordingly, inducible AML1-ETO expression is followed by apoptosis to a lower degree. Especially, AML1-ETO endows leukemic cells with the susceptibility to anti-Fas agonist antibody, ultraviolet light and camptothecin analog NSC606985-induced apoptosis with increased activation of caspase-3/8. Considering that apoptosis-enhancing effect of AML1-ETO would not be favorable to the leukemogenesis harboring the t(8;21) translocation, it must be overcome to fulfill their leukemogenic potential. Complementary to this prediction is that two AML1-ETO-carrying leukemic cells, Kasumi-1 and SKNO-1, present similar sensitivity to apoptosis induction with AML1-ETO-negative leukemic cells. Therefore, genetic and/or epigenetic screenings of apoptosis-related genes modulated by AML1-ETO deserve to be explored for understanding the mechanisms of AML1-ETO-induced leukemogenesis.

Antibodies, Monoclonal↗
PubMed2005

Quantification of outpatient management and hospitalization of patients with high-risk myelodysplastic syndrome treated with low-dose decitabine.

Intravenous low-dose 5-aza-2'-deoxycytidine (decitabine) in patients with advanced myelodysplastic syndrome (MDS) yields an approximately 50% overall response rate, including 20-25% complete remission. Decitabine-treated MDS patients can be managed as outpatients after completion of a 3-day infusion schedule. In-hospital nights (IHNs), overall survival (OS), and remaining life spent in hospital were evaluated and compared to a matched control group receiving different standard treatments. Between July 1992 and September 2001, 99 high-risk MDS patients, median age 70 years (range 49-86), were treated with low-dose decitabine. Durations of all hospitalizations were recorded. For matched-pair analysis, 44 decitabine-treated patients were matched to 44 MDS patients according to International Prognostic Scoring System classification, period of diagnosis, age, French-American-British classification, and gender. Median number of IHN across all patients was 56 and survival was 481 days, resulting in 84% of remaining life spent at home. In the matched-pair analysis, the median number of IHN was 57 in the decitabine group vs. 50 in the control group. Median survival was 400 vs. 371 days for the decitabine and control groups, respectively. Median number of remaining life spent at home was identical (83% for both groups). Matched patients who received only best supportive care (n=12) had a shorter median survival than the decitabine patients (234 vs. 400 days), and the proportion of remaining life spent at home was slightly greater (82 vs. 77%). Interestingly, matched patients with induction therapy showed comparable IHN, OS, and remaining life spent at home. In conclusion, high-risk MDS patients treated with low-dose decitabine have better survival, and spend comparable time in hospital than patients treated with supportive treatment.

Aged↗
PubMed2005

An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients.

During the last 10 years, three European phase II studies were performed to investigate the treatment of elderly patients with myelodysplastic syndrome (MDS) with low-dose 5-aza-2'-deoxycytidine (decitabine, DAC). All these European trial data were reviewed on the basis of the International Prognostic Scoring System (IPSS) risk criteria and the response criteria as recently published by an international working group. To investigate the results in a larger cohort of patients and to determine risk factors, all data were pooled with some observations from the PCH 95-06 US phase II study. The response rate in the 177 patients evaluated (median age 70 years) was 49%. The median response duration was 36 weeks, and the median survival was 15 months. Analysis of the data according to sex, age, French-American-British classification, percentage of blasts in the bone marrow, IPSS risk group, lactate dehydrogenase and cytogenetics did not reveal any factor predictive of response. Overall, 69% of patients benefited, including those with stable disease during therapy. Response duration was significantly shorter with increasing risk (according to the IPSS classification). Haemoglobin level and neutrophil count showed an inverse correlation to the IPSS classification. Univariate analysis showed a significantly inferior survival for elderly patients (>75 years of age) and for those with high levels of serum lactate dehydrogenase (LDH) (more than two times the normal values). Patients with high-risk cytogenetic abnormalities according to the IPSS risk criteria showed better overall survival than those with intermediate-risk abnormalities. When analysed according to the IPSS risk classification, high-risk patients had worse survival prospects following decitabine therapy than those with intermediate risk; however, compared to the originally reported IPPS outcomes for high-risk patients, they probably showed better survival. During the treatment period, 18% of the patients progressed towards acute leukaemia. Decitabine showed a rather low toxicity profile in this elderly patient group. In conclusion, low-dose decitabine is an active drug for the treatment of MDS patients, even for those older than 75 years with bad prognostic characteristics.

Adult↗
PubMed2005

Induction of gene expression by 5-Aza-2'-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms.

The methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR, decitabine) has therapeutic efficacy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Using microarray analysis, we investigated global changes in gene expression after 5-Aza-CdR treatment in AML. In the AML cell line OCI-AML2, Aza-CdR induced the expression of 81 out of 22 000 genes; 96 genes were downregulated (> or =2-fold change in expression). RT-PCR analysis of 10 randomly selected genes confirmed the changes of expression in AML cells. Similar results were obtained with primary AML and MDS cells after treatment with 5-Aza-CdR ex vivo and in vivo, respectively. In contrast, significantly fewer changes in gene expression and cytotoxicity were detected in normal peripheral blood mononuclear and bone marrow cells or transformed epithelial cells treated with 5-Aza-CdR. Interestingly, only 50.6% of the induced genes contain putative CpG islands in the 5' region. To further investigate the significance of promoter methylation in the induced genes, we analyzed the actual methylation status of randomly selected 5-Aza-CdR-inducible genes. We detected hypermethylation exclusively in the 5' region of the myeloperoxidase (MPO) gene. DNA methylation inversely correlated with MPO expression in newly diagnosed untreated AML patients (P< or =0.004). In contrast, all other analyzed 5-Aza-CdR-inducible genes revealed no CpG methylation in the promoter region, suggesting a methylation-independent effect of 5-Aza-CdR.

Acute Disease↗
PubMed2005

Desferrioxamine induces leukemic cell differentiation potentially by hypoxia-inducible factor-1 alpha that augments transcriptional activity of CCAAT/enhancer-binding protein-alpha.

We reported recently that cobalt chloride-simulated hypoxia and mild hypoxia modified the differentiation of human acute myeloid leukemic (AML) cells, probably acting via a hypoxia-inducible factor-1 alpha (HIF-1 alpha)-dependent mechanism. In this study, we investigated the effect of desferrioxamine (DFO), an iron chelator with 'hypoxia-mimetic' activity, on the differentiation of AML cells. The results showed that DFO at nontoxic concentrations induced the differentiation of AML cell lines NB4 and U937, as assessed by morphological criteria and differentiation-associated antigens. DFO-induced differentiation parallel to the rapid accumulation of HIF-1 alpha protein in these two cell lines. Of importance, the transient transfection of HIF-1 alpha cDNA induced U937 cells to develop the differentiation-related alterations such as growth arrest and increased CD11b expression. Furthermore, the inducible expression of chromosome translocation t(8;21)-generated leukemogenic AML1-ETO fusion gene attenuated DFO-induced differentiation of U937 cells with the decrease of CCAAT/enhancer-binding protein alpha (C/EBP alpha), a critical factor for granulocytic differentiation. Using immunoprecipitation and luciferase reporter assay, HIF-1 alpha was also shown to interact physically with and to increase the transcriptional activity of C/EBP alpha. Taken together, these results provided novel evidence for a role of HIF-1 alpha in AML cell differentiation, and suggested that C/EBP alpha might be a downstream effector for HIF-1 alpha-mediated differentiation.

Acute Disease↗
PubMed2005

Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS).

The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian-German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.

Adolescent↗
PubMed2004

Risk-adapted induction and consolidation therapy in adults with de novo AML aged </= 60 years: results of a prospective multicenter trial.

We treated 305 de novo acute myeloid leukemia (AML) patients aged </=60 years with risk-adapted therapy. Patients with CBF leukemias or normal karyotype and good response to induction I [</=5% bone marrow (BM) blasts on day 15] were considered standard risk (SR), all others as high risk (HR). Patients with t(15;17) were excluded. Chemotherapy comprised double induction followed by early consolidation. As late consolidation, SR patients received high-dose cytarabine/daunorubicin (AraC/DNR). SR patients with normal karyotype were allotransplanted from HLA-matched siblings. HR patients were allotransplanted or if no sibling donor was available autotransplanted with peripheral blood progenitor cells (PBSC) harvested after early consolidation. 89% of the SR and 60% of the HR patients achieved CR. The continuous complete remission (CCR) rate at 80 months (median follow-up: 48 months) was 48% for SR and 32% for HR. The CCR rate was 54% for t(8;21), 47% for normal karyotype, and 33% for inv(16) patients. In the HR group, the CCR rate did not differ significantly for patients with bad response to IVA-I, unfavorable karyotype, or both. Forty-five HR patients were autotransplanted (n=20) or allotransplanted (n=25). The probability of CCR was 44% for autotransplantation vs 33% for allotransplantation. In conclusion, our risk-adapted strategy produced encouraging results in SR patients. Early response to therapy is a strong prognostic factor that predicts the probability of CR and long-term outcome.

Adolescent↗
PubMed2003

Prognosis of older patients with acute myeloid leukemia receiving either induction or noncurative treatment: a single-center retrospective study.

Since few studies focus on prognostic factors in unselected elderly acute myeloid leukemia (AML) patients, a retrospective analysis of 138 consecutive patients aged >55 years (median age: 67, range: 56-89) with AML diagnosed at a single center over an 8-year period was performed: 69% had de novo AML and 31% secondary (s) AML; 67% of the patients were karyotyped. Of the patients, 73 (53%) were treated with standard induction therapy protocols and 65 (47%) received palliative treatment only. Univariate and multivariate analyses of the effects of the following factors on overall survival (OS) were performed: sex, age > or = vs <65 years, de novo vs sAML, serum (s) lactate dehydrogenase (LDH) > or = vs <400 U/l, leukocytes > or = vs <50,000/ microl, induction therapy, and karyotype. Additionally, in patients receiving induction therapy, complete remission (CR) rates and survival from CR were analyzed. CR rate was 47% [95% confidence interval (35%, 59%)], 53% (39%, 66%) in de novo AML, and 21% (5%, 51%) in sAML. After a median follow-up of 4 years, 130 deaths were observed (94%). In a univariate analysis, significant factors for longer OS were induction therapy, age <65 years, sLDH <400 U/l, and de novo AML. In a multivariate analysis, significant factors for longer OS were sLDH <400 U/l and induction therapy. However, the difference between treatment outcome may also be due to selection criteria not captured, such as performance status, comorbid conditions, wish of the patient, etc. The effects of intensive and nonintensive treatment in this patient group need to be investigated in prospective, randomized trials in which these clinical parameters of high relevance for treatment decisions in older patients are also considered.

Acute Disease↗
PubMed2003

Efficacy and safety of imatinib mesylate (Glivec) in combination with interferon-alpha (IFN-alpha) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

Imatinib has marked antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), but secondary resistance develops rapidly, reflecting the limitations of single-agent therapy. Experimental data suggest that interferon-alpha (IFN-alpha) enhances the antileukemic activity of imatinib. We therefore examined combined imatinib and low-dose IFN-alpha in six patients with Ph+ALL who were ineligible for stem cell transplantation. All patients had received imatinib for 0.5-4.8 months prior to IFN-alpha, for relapsed (n=3) or refractory (n=1) Ph+ALL or as an alternative to chemotherapy following severe treatment-related toxicity (n=2). Five patients were in hematologic remission (CR) with minimal residual disease (MRD+), one patient was refractory to imatinib. Four of the five MRD+ patients are alive in CR after a median treatment duration of 20 (11-21) months. Two of these patients are in continuous CR 21 months after imatinib was initiated, while the other two patients experienced an isolated meningeal relapse that was successfully treated with additional intrathecal chemotherapy. Sustained molecular remissions were achieved in three patients and are ongoing 13 and 10.5 months after central nervous system (CNS) relapse and 6 months after starting concurrent IFN-alpha and imatinib, respectively. Marrow relapse occurred in one of the five MRD+ patients. Combination treatment was associated with a complete marrow response of 5 months duration in the imatinib-refractory patient. Imatinib combined with low-dose IFN-alpha may achieve prolonged hematologic and molecular remissions in a subset of patients with advanced Ph+ALL, who are not candidates for allogeneic SCT. CNS prophylaxis is necessary and may enhance the antileukemic activity of imatinib and IFN-alpha.

Aged↗
PubMed2002

CD34(+) or CD34(-): which is the more primitive?

Remarkable progress has been achieved in the characterization and isolation of primitive hematopoietic stem cells (HSC). HSC represent a very small subset of hematopoietic cells and provide self-renewal, possess differentiation capacity and allow a constant supply of the entire hematopoietic cell spectrum. Until recently, CD34 has been used as a convenient marker for HSC, since CD34(+) cells have been shown to possess colony-forming potential in short-term assays, maintain long-term colony-forming potential in in vitro cultures and allow the expression and differentiation of blood cells from different hematopoietic lineages in in vivo models. Clinical and experimental protocols have targeted CD34(+) cells enriched by a variety of selection models and have readily used these for transplantation, purging and gene therapies and targets for future organ replacement. Recent studies in murine and human models, however, have indicated that CD34(-) HSC exist as well, which possess engraftment potential and distinct HSC characteristics. These studies challenge the dogma that HSC are uniformly found in the CD34(+) subset, and question whether primitive HSC are CD34(+) or CD34(-). In this review, results on murine and human CD34(+) and CD34(-) HSC, differences between them and their possible interactions are examined.

Animals↗
PubMed2001

Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cells.

BACKGROUND: Many cancers display alterations in methylation patterns of CpG islands--stretches of DNA rich in CpG dinucleotides often associated with gene promoters that are involved in initiation of gene transcription. This methylation may perturb expression of genes critical to the regulation of cell proliferation. Aberrant methylation is not limited to a few genes or to promoter regions but has been found on a genome-wide scale in a variety of neoplasias, including colorectal cancer and acute myelogenous leukemia. Our goal was to characterize, in a quantitative manner, the profiles of abnormally methylated genes that may be specific for different cancers. METHODS: Using a quantitative assay, methylation-sensitive single nucleotide primer extension (MS-SNuPE), we have analyzed the methylation levels of promoter and exonic (coding region) CpG islands of two cyclin-dependent kinase inhibitors [p15(INK4B) and p16(INK4A)] and the PAX6 gene, which encodes a transcriptional factor involved in neuronal proliferation, in DNA samples taken from patients with chronic myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, and colorectal cancer. RESULTS: De novo methylation of all three exonic loci in tumors--relative to baseline levels found in nontumor tissue or blood--was observed in hematologic neoplasias and in solid tumors as well as in normal colonic tissue. However, methylation of promoter regions was more limited. Moreover, two different patterns of promoter methylation distinguished the leukemias from colorectal cancer: p15 promoter hypermethylation was found only in the leukemias, and p16 promoter hypermethylation occurred only in colon tumors. However, we did not address this issue prospectively; therefore, such an observation is only hypothesis generating. CONCLUSIONS: The methylation patterns that we observed suggest that exonic CpG islands are more susceptible to de novo methylation than promoter islands and that methylation may be seeded in exonic regions, from which it can spread to other islands, including promoter regions. Subsequent selection of cells with a growth advantage conferred by spread of methylation into and inactivation of a particular promoter might then contribute to the genesis of a specific type of cancer.

Acute Disease↗
PubMed2001

Differentiation associated modulation of the cytokine and chemokine expression pattern in human myeloid cell lines.

Hematopoietic progenitor cell differentiation is associated with the expression of different sets of genes including those encoding membrane bound molecules and cytokines. While expression of the former has meticulously been linked to both lineage specificity and maturation stages and is routinely used in the diagnosis of human leukemias, the production of cytokines has not systematically been analyzed in this respect. Secretion of cyto- and chemokines by HPC has been discussed as a key element of autocrine regulation of cell differentiation and proliferation in normal and malignant hematopoietic cells. Hematopoietic cell lines and their in vitro generated mature progeny were used as a model to investigate the cytokine and chemokine expression pattern prior to and after induction of differentiation. We show that a variety of cytokines are produced by these cells either constitutively or upon stimulation. Low levels of TNF-alpha and IL-8 were widely expressed by immature and mature cells, while peak values of TNF-alpha were detected in promyelocytic NB4 cells, as reported previously. Induction of monocytic differentiation by various agents was associated with upregulation of IL-1 beta and IL-1ra expression, while a differentiation shift to the granulocytic lineage in the presence of retinoic acid (RA) led to a marked increase of macrophage chemoattractant protein-1 (MCP-1) producing cells. These data indicate that lineage determination as well as maturation of hematopoietic cells may not only be associated with expression of specific surface molecules but also with a distinct cytokine expression pattern. Further studies are necessary to show if this holds true for primary leukemic and normal hematopoietic cells.

Cell Differentiation↗