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M Wetzler

Publications and source records attributed to M Wetzler.

At least 55 records · Page 3Linked to original sources
PubMed1994

Leukemia inhibitory factor in long-term adherent layer cultures: increased levels of bioactive protein in leukemia and modulation by IL-4, IL-1 beta, and TNF-alpha.

In the current study, we used a monoclonal antibody-based enzyme-linked immunosorbent assay and bioassay to assess leukemia inhibitory factor (LIF) protein levels, activity, and function in supernatants of 59 adherent layers derived from acute and chronic myelogenous leukemia, myelodysplastic syndrome, and hairy cell leukemia patients and from normal controls. We demonstrate that biologically active LIF protein is constitutively produced and secreted by cultured bone marrow stromal cells from all of the studied subjects. Furthermore, various cytokines can alter endogenous LIF protein levels. Twenty-four h of exposure to recombinant human (rh) interleukin (IL) 4 (100 units/ml) significantly decreased LIF protein levels in adherent layer conditioned media [median base line level, 2.6 ng/ml; range, 1.6-8.0 ng/ml; median post rhIL-4 exposure levels, 1.9 ng/ml; range, 0.9-5.8 ng/ml (n = 7; P = 0.022)]. In contrast, rhIL-1 beta and rh tumor necrosis factor alpha consistently increased LIF protein levels. In the samples exposed to 50 units/ml rhIL-1 beta, median base line LIF level was 2.6 ng/ml; median post-LIF level was 9.0 ng/ml (n = 8; P = 0.014). In the two samples exposed to rh tumor necrosis factor alpha (200 units/ml), LIF levels increased from baseline levels of 2.6 and 2.7 ng/ml to postexposure levels of 7.7 and 12.2 ng/ml, respectively. Finally, the presence of LIF may be relevant to both normal and malignant hematopoietic processes as evidenced by: (a) LIF protein levels in adherent layer conditioned media were significantly elevated in samples from patients with a spectrum of hematological neoplasms [acute myelogenous leukemia: median level, 3.0 ng/ml (range, 1.6-11.0 ng/ml); myelodysplastic syndrome: median level, 4.5 ng/ml (range 1.4-15.5 ng/ml); hairy cell leukemia; median level, 3.5 ng/ml (range 2.2-10.3 ng/ml); chronic myelogenous leukemia-chronic phase: median level, 4.35 ng/ml (range 0.3-19.0 ng/ml); and chronic myelogenous leukemia-blast crisis: median level, 6.25 ng/ml (range 0.7-20.3 ng/ml)] as compared to samples from normal individuals (median level, 2.0 ng/ml; range, 0.7-4.6 ng/ml; P < 0.05); and (b) in normal controls, in vitro abrogation of endogenous LIF bioactivity by neutralizing antibody decreased the number of committed granulocyte-macrophage hemopoietic progenitors.

Blast Crisis↗
PubMed1994

Interleukin 4 alters human bone marrow stroma and modulates its interaction with hematopoietic progenitors.

To investigate the functional activity of interleukin 4 (IL-4) on human marrow stroma formation, normal bone marrow (BM) samples were cultured in "Dexter-type" long-term cultures in the presence and absence of IL-4. IL-4 (0.001 to 1.0 micrograms/ml) added at the initiation of culture and once weekly when the cultures were fed effaced the culture architecture. In four-week old confluent cultures smooth muscle-like and endothelial-like cells were rare, the fibronectin network and cobblestone areas were absent, and a preponderance of monocyte-macrophages characterized the adherent layer. Exposure to IL-4 reduced the numbers of CD34+ cells, colony-forming unit granulocyte-macrophage (GFU-GM) cells and burst-forming unit-erythroid (BFU-E) cells in the adherent layer, and increased their numbers in the nonadherent layer. In five of eight IL-4-containing cultures the concentrations of macrophage colony-stimulating factor (M-CSF) were increased and in two of eight IL-4-treated cultures the concentrations of tumor necrosis factor-alpha (TNF-alpha) were significantly elevated as compared to those in control cultures, whereas there were no consistent differences in the levels of either IL-6 or transforming growth factor-beta (TGF-beta). IL-1 beta and granulocyte-macrophage CSF (GM-CSF) were not detected in any culture. These data suggest that IL-4 suppresses stroma formation and alters its structure and cellular composition.

Antigens, CD↗
PubMed1993

Granulocyte-macrophage colony-stimulating factor as a cause of paraneoplastic leukaemoid reaction in advanced transitional cell carcinoma.

Increasing evidence suggests that paraneoplastic syndromes may be mediated by tumour-related cytokine release, although the specific factor(s) involved remain poorly defined. Colony-stimulating factors (CSF) and interleukins (IL) promote colony growth in semi-solid media and, when administered in recombinant form, increase blood counts in patients. However, normal serum CSF levels in individuals with physiologic blood counts and the relationship between specific serum CSF levels and paraneoplastic leukaemoid reaction are not well established. In this study, we found that normal serum levels of granulocyte-macrophage CSF (GM-CSF), as measured by ELISA, were generally < 55 pg ml-1; IL-3, < 30 pg ml-1; and granulocyte CSF (G-CSF), < 50 pg ml-1. In contrast, high levels of GM-CSF (132 pg ml-1), but not G-CSF or IL-3, were found in a patient with a transitional cell carcinoma of the renal pelvis and increased leukocytosis correlating with the tumour burden. The GM-CSF was biologically active, as demonstrated by its ability to stimulate colony growth in vitro. Based on these results it appears that autonomous production of GM-CSF is one possible pathophysiologic mechanism underlying leukaemoid reaction in cancer patients.

Aged↗
PubMed1993

Subcellular localization of Bcr, Abl, and Bcr-Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation.

We used specific antisera and immunohistochemical methods to investigate the subcellular localization and expression of Bcr, Abl, and Bcr-Abl proteins in leukemic cell lines and in fresh human leukemic and normal samples at various stages of myeloid differentiation. Earlier studies of the subcellular localization of transfected murine type IV c-Abl protein in fibroblasts have shown that this molecule resides largely in the nucleus, whereas transforming deletion variants are localized exclusively in the cytoplasm. Here, we demonstrate that the murine type IV c-Abl protein is also found in the nucleus when overexpressed in a mouse hematopoietic cell line. However, in both normal and leukemic human hematopoietic cells, c-Abl is discerned predominantly in the cytoplasm, with nuclear staining present, albeit at a lower level. In contrast, normal endogenous Bcr protein, as well as the aberrant p210BCR-ABL and p190BCR-ABL proteins consistently localize to the cytoplasm in both cell lines and fresh cells. The results with p210BCR-ABL were confirmed in a unique Ph1-positive chronic myelogenous leukemia (CML) cell line, KBM5, which lacks the normal chromosome 9 and hence the normal c-Abl product. Because the p210BCR-ABL protein appears cytoplasmic in both chronic phase and blast crisis CML cells, as does the p190BCR-ABL in Ph1-positive acute leukemia, a change in subcellular location of Bcr-Abl proteins between cytoplasm and nucleus cannot explain the different spectrum of leukemias associated with p210 and p190, nor the transition from the chronic to the acute leukemia phenotype seen in CML. Further analysis of fresh CML and normal hematopoietic bone marrow cells reveals that p210BCR-ABL, as well as the normal Bcr and Abl proteins, are expressed primarily in the early stages of myeloid maturation, and that levels of expression are reduced significantly as the cells mature to polymorphonuclear leukocytes. Similarly, a decrease in Bcr and Abl levels occurs in HL-60 cells induced by DMSO to undergo granulocytic differentiation. The action of p210BCR-ABL and its normal counterparts may, therefore, take place during the earlier stages of myeloid development.

Animals↗
PubMed1993

CML: mechanisms of disease initiation and progression.

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of the myeloid lineage. It has a progressive course typified by the transition from the chronic phase to the accelerated phase and on to blast crisis. The hallmark of CML is the translocation between chromosomes 9 and 22 that results in the chimeric BCR-ABL gene encoding p210BCR-ABL. The oncogenic potential of this protein has been validated, and it is believed that it contributes in a critical way to the initiation of CML. However, the secondary genetic forces responsible for the transition from the chronic state to the fully blastic stage are not clear. Evidence for chromosomal instability includes the clonal evolution which characterizes advanced CML. In regard to specific genetic aberrations, sporadic reports have shown alterations in H-RAS, c-MYC, retinoblastoma, and P53 genes, as well as production of p190BCR-ABL during the progression of CML. In addition, we have recently found evidence for excessive interleukin-1 beta production, acting in an autocrine and/or paracrine manner, in the more advanced stages of the disease. Taken together, current data suggest that multiple molecular pathways lead to disease progression, and that distinct subsets of genetic alterations exist in blast crisis patients.

Blast Crisis↗
PubMed1993

Ubiquitous expression of cytokines in diverse leukemias of lymphoid and myeloid lineage.

It has recently been suggested that autocrine production of hematopoietic regulatory molecules can modulate the cardinal features of many leukemic states: excessive proliferation of the neoplastic cells and suppression of the normal elements. We therefore analyzed samples obtained from 57 patients with a variety of hematologic malignancies (21, acute myelogenous leukemia; 14, acute lymphoblastic leukemia; 12, Philadelphia chromosome-positive chronic myelogenous leukemia [blast phase] or acute leukemia; 5, chronic lymphocytic leukemia; and 5, chronic myelomonocytic leukemia) for expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) transcripts on Northern blots. TNF-alpha mRNA was discerned in almost half of the samples (47%), and was expressed in some patients with every type of leukemia, except T-cell acute lymphoblastic leukemia (ALL). Expression occurred with great frequency in samples (12 of 15 [80%]) from monocytic (acute or chronic) leukemias, and from advanced chronic lymphocytic leukemia (4 of 5 samples [80%]). IL-1 beta transcripts were detected in 20 of 57 samples (35%). Its presence, like that of TNF-alpha, was ubiquitous, and only chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia cells consistently failed to produce IL-1 beta message. Therefore it appears that TNF-alpha and/or IL-1 beta mRNA can be found in the leukemic cells from a substantial subset of patients with B cell-derived acute lymphoblastic leukemia as well as with chronic and acute myeloid, monocytic or lymphocytic leukemias. Because these cytokines have potent direct and indirect effects on normal and malignant hematopoiesis, their widespread constitutive expression by neoplastic blood cells may play a fundamental role in driving the leukemic process.

Blotting, Northern↗
PubMed1993

Suppression of chronic myelogenous leukemia colony growth by interleukin-4.

Interleukin-4 (IL-4) is a cytokine with pleiotropic activities. In normal bone marrow cultures grown in the presence of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), IL-4 suppresses granulocyte-macrophage colony-forming unit (CFU-GM) proliferation but it enhances the colony-stimulatory effect of granulocyte colony-stimulating factor (G-CSF). We studied the effect of IL-4 on chronic myelogenous leukemia (CML) bone marrow or peripheral blood cells from 30 patients using the CFU-granulocyte-erythrocyte-monocyte-megakaryocyte colony culture assay. In several repetitive experiments, IL-4 inhibited CFU-GM colony replication by 24 to 65% in a dose-dependent fashion at concentrations ranging from 0.01 to 10 micrograms/ml when patients' cells were cultured in the presence of erythropoietin alone or with phytohemagglutinin-conditioned medium, GM-CSF, or IL-3. The addition of 100 U/ml of IL-1 beta to the CML cultures partially reversed the inhibitory effect of IL-4. Incubation of CML low-density peripheral blood cells with IL-4 resulted in down-regulation of IL-1 beta and IL-6 production in three of four samples, suggesting that the suppressive effect of IL-4 is mediated by inhibition of IL-1 and by other mechanisms including inhibition of IL-6 production. In contrast to the stimulatory effect exerted by IL-4 on G-CSF-dependent CFU-GM progenitor proliferation in normal marrow, the addition of IL-4 to CML cultures grown in the presence of G-CSF resulted in a divergent effect: suppression of CML CFU-GM in two, stimulation in three, and no significant effect in two CML patients' samples. It is therefore possible that IL-4 may have an in vivo antiproliferative effect in a subpopulation of CML patients.

Adult↗
PubMed1992

Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors.

Interleukin-1 (IL-1) has recently been reported to play an important role in acute myelogenous leukemia (AML) blast proliferation. We therefore investigated the effect of soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) on the growth of AML bone marrow blast progenitors from 25 patients. In the AML blast colony culture assay, sIL-1R and IL-1RA inhibited blast colony-forming cell replication in a dose-dependent fashion, at concentrations ranging from 10 to 500 ng/mL (sIL-1R) and 10 to 1,000 ng/mL (IL-1RA), and their inhibitory effect was partially reversed by IL-1 beta. A similar inhibitory effect was also noted with the use of anti-IL-1 beta neutralizing antibodies. When AML blast progenitors were grown either in the presence of fetal calf serum (FCS) alone or with one of the following: phytohemagglutinin leukocyte-conditioned medium (PHA-LCM), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), or stem cell factor (SCF), addition of 100 ng/mL sIL-1R or IL-1RA inhibited blast colony formation by 3% to 96% and 2% to 97%, respectively. In sharp contrast, neither of these IL-1-inhibitory molecules significantly inhibited proliferation of normal marrow hematopoietic progenitors. Lysates of 2 x 10(7) low-density AML marrow cells were tested for intrinsic IL-1 beta content using an enzyme-linked immunoadsorbant assay (ELISA). Samples from five of six patients showed high concentrations (ranging from 501 to 2,041 pg), whereas 2 x 10(7) cells from two normal marrow aspirates yielded 54.6 pg of IL-1 beta. AML blast colony-forming cells from all six patients were inhibited by sIL-1R, IL-1RA, or both. Incubation of nine samples of AML low-density cells with either sIL-1R or IL-1RA reduced GM-CSF concentrations in cell lysates, and supernatants from nine (P less than .01) and six samples (P less than .037), respectively, and G-CSF concentration in lysates from six of nine samples (P less than .03), and in supernatants from five of six samples (P less than .06) when studied by ELISAs. Our data implicate IL-1 in AML blast proliferation and suggest the potential benefits of using IL-1-inhibitory molecules in future therapies for AML.

Adult↗
PubMed1992

Interferon-stimulated genes in interferon-sensitive and -resistant chronic myelogenous leukemia patients.

alpha-Interferon induces hematological and cytogenetic remissions in some individuals with newly diagnosed Philadelphia-positive chronic myelogenous leukemia. However, interferon-resistant disease occurs in a consistent patient subset (primary resistance) and develops during therapy in additional patients (secondary resistance). Several alpha-interferon-inducible genes have been characterized. In interferon-resistant cell line variants, defects in these genes have been implicated in the mechanisms mediating resistance. We have, therefore, evaluated mRNA expression of four interferon-stimulated genes (ISGs) following alpha-interferon therapy. Twenty-seven chronic myelogenous leukemia patients (ten interferon-sensitive patients, 17 interferon-resistant patients) were studied. Peripheral blood samples were collected prior to and 1 to 7 days after starting interferon therapy and analyzed for the expression of 2'-5' oligoadenylate synthetase, ISG-15, ISG-54, and 6-16 transcripts. Following therapy with alpha-interferon, 2'-5' oligoadenylate synthetase, ISG-54, and 6-16 transcripts were discerned in all patients regardless of their response to interferon. The ISG-15 message was detected in eight of nine interferon-sensitive and in 15 of 16 interferon-resistant patients, as well. Overall, no consistent defect in the ISG system could be identified. Therefore, lack of induction of these genes cannot explain resistance to alpha-interferon in chronic myelogenous leukemia patients. Other mechanisms such as posttranslational modification, leading to defects in the ISG corresponding proteins, may play a role in the development of resistance.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

The modulatory hematopoietic activities of leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a multi-potential cytokine which has been implicated in the hematopoietic regulatory machinery. For example, we have found that LIF is constitutively expressed in marrow stroma. Other investigators have reported that LIF affects remodeling of bone, and that, in concert with other growth factors, it stimulates hematopoietic stem cell proliferation. Moreover, in vivo animal trials reveal that, at high doses, administration of LIF induces myelosclerosis whereas, at lower doses, megakaryocytosis and thrombocytosis with reduced bone marrow cellularity and marrow lymphopenia are observed. Therefore, the role of LIF in the pathogenesis of myeloproliferative disorders such as myelofibrosis and sclerosis merits investigation. Further, its megakaryocytic stimulatory properties suggest that LIF may be exploitable in the clinic to enhance platelet production.

Animals↗
PubMed1991

Alteration in bone marrow adherent layer growth factor expression: a novel mechanism of chronic myelogenous leukemia progression.

Philadelphia chromosome1 positive (Ph1) chronic myelogenous leukemia (CML) is characterized by metamorphosis of the chronic phase to blastic crisis. However, cellular events associated with this transition are poorly understood. To examine the possible participation of hematopoietic growth factors in this process, we studied growth factor expression in adherent layers of bone marrows derived from CML Ph1 patients in various stages of the disease. Interleukin-1 beta (IL-1 beta) and IL-6 mRNA were expressed in five of six patients, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in one of six patients with myeloid/undifferentiated blast crisis. In addition, leukemia inhibitory factor (LIF) expression was increased in four of six patients with myeloid/undifferentiated blast crisis phase of the disease. IL-1 beta was also detected in bone marrow adherent layer conditioned medium from two of these patients. These results were in sharp contrast to the lack of detectable levels of uninduced IL-1 beta, IL-6, and GM-CSF mRNA, in samples derived from 4 patients in lymphoid blastic crisis, 3 in accelerated, and 11 in chronic phases of the disease, or from normal controls. The possibility of a paracrine loop formation, whereby the adherent layers representing the bone marrow stroma are induced to express hematopoietic growth factors, was supported by our finding IL-1 beta mRNA expression in the leukemic blast cells in three of four studied patients in blast crisis and IL-1 beta protein production in seven of eight patients studied. Finally, coculturing CML blast crisis cells onto pre-established adherent layers induced the expression of both IL-1 beta and IL-6 genes. From this preliminary study, it appears that abnormal expression of growth factors is a common event with CML Ph1 progression. We hypothesize that IL-1 beta generated by the transformed malignant clone stimulates the marrow stroma to produce various growth factors, and that this process may play a role in disease progression.

Blast Crisis↗
PubMed1991

Suppression of chronic myelogenous leukemia colony growth by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors: a novel application for inhibitors of IL-1 activity.

In this study, we investigated the role of interleukin-1 beta (IL-1 beta) in the malignant evolution of chronic myelogenous leukemia (CML) and the functional activity of IL-1 inhibitors. Bone marrow (BM) and peripheral blood (PB) low-density cells from 38 CML patients were studied in the colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte colony culture assay. Samples from patients with early stage, interferon-alpha (IFN)-sensitive disease formed hematopoietic colonies in the presence of fetal calf serum (FCS), erythropoietin (Epo), and one of the following: granulocyte-macrophage colony-stimulating factor (10 ng/mL), IL-3 (15 ng/mL), both, or phytohemagglutinin-conditioned medium. The addition of IL-1 beta augmented IFN-sensitive CML colony growth in a dose-dependent manner at concentrations of 10 to 100 U/mL. In sharp contrast, addition of the above growth factors did not augment the colony growth-promoting effect of FCS and Epo in samples from IFN-resistant patients; further, adherent cell fractionation or T-lymphocyte depletion attenuated the "autonomous" colony growth. Lysates of 2.5 x 10(7) low-density cells from each of six IFN-resistant and six IFN-sensitive CML patients and three normal volunteers were tested for intrinsic IL-1 beta content in an enzyme-linked immunosorbent assay and yielded a mean of 610 pg, 54.6 pg, and 49.4 pg of IL-1 beta, respectively (P less than .045). Interestingly, both soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) at concentrations of 5 to 100 ng/mL (sIL-1R) and 10 to 500 ng/mL (IL-1RA) inhibited CML colony growth in a dose-dependent fashion, with maximal inhibition of 64% and 65%, respectively. A similar effect was noted with the use of anti-IL-1 beta neutralizing antibodies. These data implicate IL-1 beta in CML disease progression and suggest that the inhibitory effects of molecules such as sIL-1R and IL-1RA could conceivably be the basis of a novel therapeutic strategy against this disorder.

Adolescent↗
PubMed1991

LIF: not just a leukemia inhibitory factor.

Increasingly it seems that many cytokines are pleiotropic, and individual molecules may have critical roles in several different organ systems. LIF exemplifies this phenomenon: it influences embryogenesis, bone and lipid metabolism, and hematopoietic and nervous system function. Many of LIF's effects are reminiscent of those of IL-1, TNF, and TGF-beta. Further, even within a single system, LIF can display totally different effects, i.e. induction of differentiation of one leukemic cell line vs. stimulation of proliferation of another. The corollary to these observations is that there appears to be many parallels in developmental systems. For instance, in the case of neuronal "lineage commitment," the events that relate to migration of neural crest cells along various pathways and their ultimate arrest in different locales demonstrate sufficient analogies to hematopoietic lineage commitment phenomena that, in a provocative review, Anderson coined the term "neuropoiesis". This type of analogy becomes even more intriguing when one realizes that some of the same molecules are regulating neuronal and hematopoietic "lineage" proliferation and differentiation. In this respect, several interleukins in addition to LIF are important in neuronal development, and nerve growth factor turns out to also be a hematopoietic regulatory molecule. Similar parallels are enacted in other organ systems as well. The mediation of identical effects by distinct cytokines bound to unique receptors could conceivably be explained by receptor transmodulation or by overlapping signaling sequences. It is nevertheless also unclear how a single cytokine attached to a single receptor can accomplish varied and opposing effects, although divergent intracellular signaling mechanisms could account for some of these phenomena. Yet another enigma relates to how cells from one system can be properly influenced by a pleiotropic molecule such as LIF without significant "cross-effects" on other potentially responsive systems. Cytokine production that is restricted to certain developmental stages, or very localized distribution and spheres of influence within a microenvironment, could be explanatory. The findings of Rathjan and colleagues, i.e. that LIF exists as both a diffusible molecule and as a molecule incorporated into the extracellular matrix, is of special interest in relation to the above questions. Indeed, the distinctions between the roles of diffusible and immobilized signaling molecules could be crucial to the multiplicity of LIF's actions. Diffusible regulatory factors allow communication between spatially separated cells. Cellular responsiveness to such factors is dictated by the presence of appropriate receptors and postreceptor machinery.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Constitutive expression of leukemia inhibitory factor RNA by human bone marrow stromal cells and modulation by IL-1, TNF-alpha, and TGF-beta.

Recent in vitro studies indicate that bone marrow mesenchymal elements, residing in close proximity to hematopoietic cell populations, elaborate a network of cytokines that are, at least partially, responsible for modulating the growth and maturation of the latter compartment. Leukemia inhibitory factor (LIF), a molecule with both positive and negative regulatory activities, has been implicated in murine embryogenesis and hematopoiesis. We demonstrate that cultured normal human bone marrow stromal cells constitutively express LIF message. Further, exposure of these cells to other hematopoietic modulators including interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) (but not interferon-alpha [IFN alpha]) increases the level of LIF RNA. Interestingly, cultured stromal cells derived from three of four patients with chronic myelogenous leukemia showed enhanced LIF expression. These observations suggest that LIF may participate, either alone or through interaction with other cytokines, in the bone marrow microenvironment-mediated influence on both normal and malignant hematopoietic processes.

Bone Marrow↗
PubMed1990

Constitutive and induced expression of growth factors in normal and chronic phase chronic myelogenous leukemia Ph1 bone marrow stroma.

Study of growth factor RNA levels in the stromal cells derived from the adherent layer of long-term bone marrow culture demonstrated constitutive expression of transforming growth factor beta 1 (TGF-beta 1) and macrophage colony-stimulating factor. These cells did not express granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interleukin (IL) 1 alpha, IL-1 beta, IL-3, and IL-6. However, granulocyte colony-stimulating factor expression could be induced by recombinant human IL-1 beta; while IL-6 could be induced by both IL-1 beta and tumor necrosis factor-alpha. No differences could be detected between adherent layers established from normal and benign phase Ph1 chronic myelogenous leukemia bone marrow. The uninduced expression of TGF-beta 1, a potent hematopoietic cell growth inhibitor, suggests that stromal cells play an inherent role in regulating the proliferation of adjacent bone marrow hematopoietic progenitor cells. However, a defect in stromal TGF-beta 1 production cannot account for the profoundly expanded myeloid compartment in chronic phase chronic myelogenous leukemia. In contrast to the constitutive expression of TGF-beta 1 and macrophage colony-stimulating factor, hematopoietic growth factors are only expressed following a proper stimulation.

Biological Factors↗