Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the growth of hematopoietic progenitors in normal donors and in patients with hematologic malignancies now designed as clonal disorders of multipotential stem cells. TGF-beta 1 at 80 pM exhibited differential effects on the normal hematopoietic progenitors when cells were stimulated with different growth factors, such as G-CSF, GM-CSF, interleukin-3 (IL-3), or stem cell factor (SCF). The suppressive effect by TGF-beta 1 was increased for growth with GM-CSF, IL-3, and SCF, and growth with G-CSF was unaffected in hematologic malignancies, TGF-beta 1 suppression for growth with G-CSF was increased for essential thrombocythemia (ET) and polycythemia vera; chronic myelogenous leukemia (CML) in chronic phase; CML in accelerated phase; CML in myeloid crisis; myelodysplastic syndrome (MDS) in refractory anemia; MDS in refractory anemia with an excess of blasts; and acute myeloblastic leukemia (AML). In CML-myeloid crisis and AML, TGF-beta 1 almost completely abolished the growth, with some patient-to-patient variation. The mean ED50s for the growth of leukemic blast progenitors were 1.6, 1.2, 0.7, and 0.2 pM in the presence of G-CSF, GM-CSF, IL-3, and SCF, respectively, c-myc and c-myb antisense oligonucleotides significantly suppressed the growth of leukemic blast progenitors, but not that of clonogenic cells from normal donors and patients with ET. We also demonstrated that TGF-beta 1 inhibits mRNA expression by AML blasts for c-myc and/or c-myb. When the data are taken together, growth suppression by TGF-beta 1 appears to increase with the progression of clonal evolution in hematologic malignancies.
 ...
PMID:Differential effects of TGF-beta 1 on normal and leukemic human hematopoietic cell proliferation. 754 18

To confirm the reported correlation of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) serum concentrations with nonhematologic toxicity after cytotoxic chemotherapy and to examine their possible effects on hematopoiesis, we evaluated serum TNF-alpha and IL-6 concentrations every 3 days during 21 chemotherapy cycles in 11 patients with acute myelogenous leukemia (AML) and one patient with chronic myelogenous leukemia in blast crisis (CML-BC). All patients developed grade IV hematologic toxicity. In 13 patient cycles, grade III-IV nonhematologic toxicity developed: hepatic (nine), pulmonary (six), and stomatitis (five). In these patient cycles, IL-6 concentrations increased from 10.1 pg/mL (4.6-15.6, 95% CI) before nonhematologic toxicity to 64.8 (5.3-124.2, 95% CI) at the onset of toxicity (p = 0.02). TNF-alpha concentrations were not detectable before nonhematologic toxicity but increased to 20.4 pg/mL (not detectable [ND]-45.5, 95% CI) at the onset of grade III-IV toxicity. In six patient cycles, grade II nonhematologic toxicity developed: hepatic (five), pulmonary (one), and stomatitis (two). In these six, IL-6 concentrations increased from 12.1 pg/mL (6.8-17.4, 95% CI) before toxicity to 21.4 (11-31.8, 95% CI) at the onset of toxicity (p = 0.03). TNF-alpha concentrations were detectable in one patient cycle before toxicity and detectable in only two patient cycles at the onset of toxicity. The peak IL-6 and TNF-alpha concentrations did not correlate with the onset of nonhematologic toxicity in 87% of patient cycles. In patient cycles with a cumulative IL-6 area-under-the-serum concentration vs. time curve (AUC) > 1000 pg/mL.d, platelet recovery (> 30 x 10(9)/L and platelet transfusion-independent) occurred earlier at 21.9 days (18.7-25.1, 95% CI) compared to the 30.6 days (23.6-37.5, 95% CI, p = 0.02) in patient cycles with an IL-6 AUC < 1000 pg/mL.d. Patient cycles with a cumulative TNF-alpha AUC > 150 pg/mL.d required a mean of 17.5 units of red blood cells (RBCs) (9.3-25.7, 95% CI) compared to patient cycles with an AUC < 150 pg/mL.d, which required only 8.9 units of RBCs (6.2-11.7, 95% CI, p = 0.03). The peak concentration and AUC for IL-6 and TNF-alpha were not significantly different between those receiving growth factors (G-CSF, six; GM-CSF, one) and those not receiving growth factors (14). Endogenous IL-6 and TNF-alpha serum concentrations increase in patients who experience nonhematologic toxicity and correlate with hematologic recovery after chemotherapy.
 ...
PMID:The influence of serum tumor necrosis factor-alpha and interleukin-6 concentrations on nonhematologic toxicity and hematologic recovery in patients with acute myelogenous leukemia. 758 79

Clonogenic cell culture assay was used to evaluate the effect of mast cell growth factor (MGF) on peripheral blood granulocyte-macrophage (GM) progenitors in 26 patients with myeloproliferative disorders (MPDs). MGF alone had a statistically significant stimulatory effect on GM colony formation, as also did interleukin-3 (IL-3) and GM colony-stimulating factor (GM-CSF), although the progenitors could form colonies spontaneously as well. When MGF was combined with either IL-3 or GM-CSF the effect was additive and was as great as that achieved with a mixture of IL-3, GM-CSF, G-CSF and IL-6. The highest colony-forming capacity of all was seen when MGF was added to the above mixture. Within the subgroups of MPDs, the stimulatory effect of MGF was significant in polycythemia vera (PV), essential thrombocythosis (ET) and chronic myelogenous leukemia (CML). MGF was the most potent single factor in PV, while GM-CSF was most effective in idiopathic myelofibrosis and both IL-3 and GM-CSF in CML. The fact that the ability of MGF to induce colony growth varied between the subgroups of MPDs may mean that the target progenitors in these diseases are biologically different. In conclusion, MGF, either alone or with others, was a potent growth factor for GM progenitors in MPDs.
 ...
PMID:The effect of mast cell growth factor on peripheral blood granulocyte-macrophage colony-forming cells in methylcellulose in myeloproliferative disorders. 758 39

Lineage-negative (lin-) normal and chronic myelogenous leukemia (CML) marrow blast populations were obtained by negative selection and subsequently separated on the basis of size by velocity sedimentation. The three subpopulations of lin- blasts obtained were enriched for F8 (the more primitive small blasts), F11 (blasts intermediate in size), and F13 (the more mature large blasts). We examined the morphological and phenotypic characteristics and cell cycle status of the subpopulations and determined the responsiveness of granulocyte-monocyte progenitors (colony-forming units/granulocyte-macrophage) derived from each subpopulation to mast cell growth factor in combination with granulocyte (G-CSF) or granulocyte-macrophage (GM-CSF) colony-stimulating factors alone and in combination. Morphological assessment revealed that an increased proportion of CML lin- blasts exhibited early cytoplasmic maturation as evidenced by the appearance of azurophilic (nonspecific) granules in the cytoplasm. Although the percentages of CML and normal small blasts expressing CD34 were similar, the proportion of CML lin- blasts expressing CD34 declined in the intermediate and more mature large lin- blast subpopulations by about 50%, whereas the percentage of CD34+ normal blasts remained essentially the same, indicating an earlier loss of CD34 expression by CML lin- blasts. In addition, the percentages of CML small blasts expressing CD33 were higher than normal (26-61% versus 0-16%, respectively), indicating that a higher proportion of CML small lin- blasts had a more mature phenotype. Mast cell growth factor addition to cultures stimulated by G-CSF, GM-CSF, or G-CSF plus GM-CSF, exerted the greatest synergistic effect (increased colony number and size) in the normal small and intermediate lin- blast cultures, but mast cell growth factor had considerably less effect, or no effect, in cultures of comparable CML subpopulations, indicating that CML lin- progenitors had a somewhat lower requirement for multiple growth factors. The findings suggest that the differences observed between normal and CML marrow subpopulations are proportional differences and that a greater proportion of CML lin- blast subpopulations exhibit characteristics associated with a more advanced stage of maturation than comparable normal lin- blast subpopulations.
 ...
PMID:Characterization of lineage-negative blast subpopulations derived from normal and chronic myelogenous leukemia bone marrows and determination of their responsiveness to human c-kit ligand. 767 76

We describe a patient with acute nonlymphocytic leukemia (ANLL) and isochromosome 17q as the sole cytogenetic abnormality. ANNL with i(17q) may represent a distinct entity with certain clinical features, such as male sex, hepatosplenomegaly, and characteristic findings in bone marrow (BM) cytology, including hypercellularity, marked basophilia and eosinophilia, and massive increase in abnormal megakaryocytes. Molecular studies of peripheral blood (PB) cells of our patient, by polymerase chain reaction (PCR) analysis, showed expression of the GCSF gene, which is located on 17q. Southern blots hybridized with a GCSF probe showed no rearrangement of this gene as has been described in some patients with i(17q) positive chronic myeloid leukemia (CML).
 ...
PMID:GCSF gene is expressed but not rearranged in a patient with isochromosome 17q positive acute nonlymphocytic leukemia. 768 96

We studied the effects of recombinant human stem cell factor (SCF) on the growth of leukemic blast progenitors obtained from 27 acute non-lymphocytic leukemia (ANLL) patients and 1 chronic myelocytic leukemia patient in myeloid crisis; the effects varied among the patients. While SCF did not have stimulatory effects in the cells of 7 patients, it stimulated primary and secondary blast colony formation in methylcellulose culture and the recovery of clonogenic cells in suspension cultures from 21 patients. SCF stimulated leukemic blast progenitors in a manner almost comparable to or more prominently than that of other CSFs, namely, IL-3, GM-CSF, and G-CSF, in 9 patients. One patient responded to SCF but not to the other CSFs. In another 11 patients, SCF was less effective on leukemic blast progenitors than the other CSFs tested. To explain the variable effects of SCF, we investigated the relation between the phenotype of leukemic blasts and responsiveness to this agent; the response was significantly higher in patients with CD34-positive blasts than in those with CD34-negative blasts. These results imply that responsiveness to SCF differs among leukemic blast progenitors originating at different hematopoietic stages. In some ANLL patients, SCF showed synergy with other CSFs, suggesting that SCF may be involved in the cytokine network affecting leukemic hematopoiesis.
 ...
PMID:Effects of stem cell factor (SCF) on the in vitro growth of leukemic blast progenitors in acute non-lymphocytic leukemia. 769 28

The effects of interferon-gamma (IFN-gamma) and/or tumor necrosis factor-alpha (TNF-alpha) on the growth of leukemic blast progenitors in 6 acute myeloblastic leukemia (AML) patients, 1 chronic myelocytic leukemia (CML) patient in blast crisis and a granulocyte colony-stimulating factor-(G-CSF-) dependent OCI/AML1a cell line established from an AML patient, were studied. Cells of fresh blood samples and the OCI-AML1a cell line were cultured in methylcellulose media and suspension culture in the presence of G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) supplemented as a growth stimulatory factor. Both cytokines suppressed the primary and secondary colony formation in methylcellulose culture of leukemic blast progenitors. The recovery of clonogenic cells in suspension culture was also suppressed by IFN-gamma and TNF-alpha. The primary colony formation in methylcellulose reflects the terminal divisions of leukemic blast progenitors, while the secondary colony formation in methylcellulose and the clonogenic cell recovery in suspension have been considered to reflect their self-renewal capacity. Therefore, IFN-gamma and TNF-alpha are considered to be effective in suppressing not only the terminal divisions but also self-renewal of leukemic blast progenitors. When both cytokines were added simultaneously to cultures, the suppressive effect of each cytokine was enhanced. The results may suggest the effectiveness of IFN-gamma and TNF-alpha in the treatment of leukemia.
 ...
PMID:Combined effect of interferon-gamma and tumor necrosis factor-alpha causing suppression of leukemic blast progenitors in acute myeloblastic leukemia. 769 1

We have previously shown that long-term cultures of adherent layers derived from patients with chronic myelogenous leukemia in blast crisis express high levels of interleukin (IL)-1 beta and that this cytokine may participate in disease progression. In this study, we analyzed cytokine expression in bone marrow adherent layers derived from patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). IL-6 messenger RNA (mRNA) was expressed in adherent layers established from four of nine MDS patients, and from 10 of 17 AML patients (including all four individuals in whom AML had evolved from an antecedent MDS state). Similarly, IL-1 beta mRNA was expressed in adherent layers derived from two of nine MDS patients and from three of 17 AML patients. Cultures from two of 10 AML patients who expressed IL-6 also expressed granulocyte (G) colony-stimulating factor (CSF) mRNA. In contrast, IL-1 beta, IL-6, and G-CSF mRNA were not discernible in adherent layers from any of 14 normal volunteers. Transforming growth factor-beta 1, macrophage (M) CSF, IL-7, and leukemia inhibitory factor mRNA as well as IL-6 protein were constitutively expressed in adherent layers derived from both MDS patients, AML patients, and normal bone marrows, whereas IL-1 alpha, tumor necrosis factor-alpha, and GM-CSF were not expressed in either the normal-, MDS- or AML-derived adherent layers. These results indicate that cultured stroma from a subset of MDS and AML patients produce IL-1 beta and/or IL-6. Although, exposure of adherent layers to exogenous IL-1 beta was able to induce IL-6 expression, in 9 of the 14 samples constitutively expressing cytokines, IL-6 transcript levels were elevated without a concomitant increase in IL-1 beta, suggesting that IL-6 transcription was independently dysregulated.
 ...
PMID:Cytokine expression in adherent layers from patients with myelodysplastic syndrome and acute myelogenous leukemia. 783 15

I investigated the effects of a tyrosine phosphatase inhibitor, orthovanadate, on the proliferation of normal and CML hematopoietic progenitor cells stimulated by different colony stimulating factors. Orthovanadate decreased CFU-GM colony formation from normal bone marrow cells stimulated by IL-3 and GM-CSF in a dose dependent manner, except for G-CSF. But, BFU-E colony formation was not affected by the treatment with orthovanadate. In CML cells, CFU-GM colony formation was relatively more resistant to orthovanadate than that in normal bone marrow cells and orthovanadate, surprisingly, increased BFU-E colony formation. Western blot analysis showed that preincubation of CML cells with orthovanadate resulted in the enhancement of tyrosine-phosphorylation of p65 mainly, when stimulated with EPO. These results suggest that the second messenger system of IL-3, G-CSF, GM-CSF, and EPO in progenitor cells in CML is different from that in normal progenitor cells and that there is big difference in the second messenger system between myeloid and erythroid progenitor cells in CML cells.
 ...
PMID:[Roles of tyrosine phosphorylation in the proliferation of leukemic hematopoietic stem cells--analysis using a tyrosine phosphatase inhibitor]. 786 59

Presently the following cytokines are applied in allogeneic bone marrow transplantation: GM-CSF (granulocyte/macrophage colony stimulating factor), G-CSF (granulocyte colony stimulating factor), interleukin 3 (IL-3) and interferon-alfa (IFN-alfa). GM-CSF and G-CSF applied after bone marrow transplantation accelerate the granulopoietic reconstitution, whereas IL-3 in addition exerts an effect on platelet recovery. These growth factors show also high efficiency in the therapy of graft failure. INF-alfa is used early after allogeneic bone marrow transplantation in patients with hig risk for relapse. This cytokin is also very effective as single therapy or together with marrow donor leukocyte infusions for the treatment of patients with chronic myeloid leukemia in relapse after allogeneic bone marrow transplantation.
 ...
PMID:[Use of cytokines in allogeneic bone marrow transplantation]. 806 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>