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)

Mutations of the p53 tumour suppressor gene occur in 20% of chronic myeloid leukaemia (CML) patients in blastic crisis, but it is still uncertain whether this inactivation plays a role in the pathogenesis of blastic transformation or in maintaining the leukaemic proliferation in CML, as it does in several solid tumours. We have previously shown that more than 50% of both normal and CML CD34+ cells express the p53 protein. However, haemopoietic cells at different phases of the cell cycle express p53 with different conformations, suggesting that the function of p53 may be closely regulated during the cell cycle. In order to elucidate the mechanism by which p53 suppresses cell proliferation, we evaluated the effects of inhibiting p53 expression on cell cycle and cell kinetics of chronic phase CML (n = 12) and normal (n = 7) bone marrow light-density cells and purified CD34+ progenitors by using an 18-mer modified antisense oligonucleotide which targets the region covering the six base pairs immediately before the first codon and the first four coding codons of p53. We found that the number of cells positive for the cell cycle-specific nuclear antigen Ki67 and for the BrdU monoclonal antibody (McAb) was significantly increased after p53 antisense olignucleotide treatment. At the same time, p53 protein expression was completely abrogated in both light-density and CD34+ cells. In addition, DNA analysis by flow cytometry demonstrated that the number of cells in quiescent phases of the cell cycle (G0-G1) was significantly decreased after exposure of light-density cells to p53 antisense oligomers, whereas the number of cells in S or G2-M phases was increased. Furthermore, the longer the incubation time the higher the increase in cell proliferation. Treatment of CML, cells with p53 antisense oligomers also resulted in significantly increased numbers of CFU-GM colonies. Our data suggest that p53 is a negative regulator of cell proliferation and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. We can further speculate that the loss of p53 function, at the time of blastic crisis of CML, may play a role, in combination with other genetic changes (p210 BCR/ABL, Rb gene abnormality, others to be defined), in inducing disturbances in cell proliferation, differentiation, and apoptosis.
 ...
PMID:Modulation of cell kinetics and cell cycle status by treating CD34+ chronic myeloid leukaemia cells with p53 antisense phosphorothioate oligonucleotides. 778

Both gamma- and alpha-interferons (IFNs) have been shown to induce clinical responses in chronic myelogenous leukemia (CML). The mechanisms behind these effects are not known. In chronic phase CML, granulocytic progenitors normally found in the bone marrow only, are found extramedullary. A defect in the adhesion of CML cells, that may be responsible for this finding, has been described earlier. In this study, we have investigated whether IFN can restore the defect in CML cell adhesion. It was found that gamma-, but not alpha-IFN, strongly induced the adhesion of CML cells to other cells and to plastic in a majority of the patients. In parallel, an induction in the expression of the adhesion molecules ICAM-1 and LFA-1 was found, and blocking of these molecules by antibodies abolished the effect. The ability of gamma-IFN to restore the adhesive property of CML cells may add to the antitumor effects observed with gamma-IFN therapy in CML.
 ...
PMID:Gamma-IFN induced cell adhesion in chronic myelogenous leukemia cells. 790 42

Eighteen patients with chronic myelogenous leukemia (CML) in chronic (9 patients) or advanced phases (9 patients) underwent autologous bone marrow transplantation (BMT) with a preparative regimen using high doses of cyclophosphamide, etoposide and total body irradiation (CY-VP16-TBI): cyclophosphamide 60 mg/kg daily on days 1 and 2; VP16 250 mg/m2 twice daily on days 1-3 and TBI 1020 cGy in six fractionated doses on days 5-7. Autologous marrow cells were reinfused on day 8. Three of the 8 patients in late chronic phase Philadelphia (Ph) chromosome-positive CML (37%) achieved a cytogenetic response, with Ph suppression to 25%, 29% and 44% Ph-positive metaphases, respectively, and lasting for 11, 1 and 3 months, respectively. The median duration of chronic phase following BMT was 26+ months (range 2-33+ months). One patient with Ph-negative, BCR-rearranged, chronic phase CML had a decrease of the BCR-rearranged band to 10% of pretreatment levels, which persisted for 6 months. None of the 9 patients with advanced CML phases (5 in second chronic, 1 in blastic, 3 in accelerated) achieved meaningful cytogenetic responses. Their median survival was 7 months from the time of BMT. Toxicities were mostly related to myelosuppression, particularly thrombocytopenia. Febrile episodes developed in 16 patients (89%). Treatment-related deaths occurred in 2 patients (11%). In summary, autologous BMT using a TBI-containing regimen had acceptable toxicity. Future investigations will evaluate the additional benefit of purged autologous stem cell transplantation in patients with chronic phase CML.
 ...
PMID:High doses of cyclophosphamide, etoposide and total body irradiation followed by autologous stem cell transplantation in the management of patients with chronic myelogenous leukemia. 795 Nov 20

We describe four patients who developed severe thrombocytopenia which progressed to aplasia after the use of alpha-interferon in maintenance therapy of chronic phase CML after busulphan induction. On reviewing over 400 patients in the MRC CML III trial we found that there is a risk of cytopenia developing after busulphan therapy and a lesser risk of cytopenias developing after alpha-interferon therapy. If the therapies are given in a sequential fashion the risk of cytopenia developing appears to be additive, may be pronounced, and may lead to clinically significant problems. Hydroxyurea alone does not lead to sustained cytopenia. Care should be taken to ensure that counts are stable after the use of busulphan before starting alpha-interferon as maintenance therapy.
 ...
PMID:Severe cytopenias associated with the sequential use of busulphan and interferon-alpha in chronic myeloid leukaemia. 801 52

Various lines of evidence suggest that substantial numbers of very primitive normal hematopoietic cells persist in the marrow of most patients with CML, despite the presence of an expanded Philadelphia-Chromosome (Ph) positive population, and that normal clones might, in certain circumstances, have a proliferative advantage over leukemic populations. We have recently demonstrated in 5/8 CML patients with blastic phase (BP) that the blood progenitor cells/(BPC) harvested during early recovery from marrow aplasia were Ph-negative on cytogenetic analysis, suggesting that leukapheresis may provide a useful source of 'normal' progenitors for subsequent reinfusions. We report here an update on 40 patients with Ph + CML and 9 patients with ALL in first or subsequent relapses with associated cytogenetic translocations including t(8;14) t(4;8) t(4;11) and t(9;22). All these patients received intensive conventional chemotherapy and during early recovery from marrow aplasia, when the WBC reached 0.5-2.0 x 10(9)/L, BPC were collected by 4-8 leukapheresis and tested for the persistence of the marker translocations and, when possible, for the presence of the hybrid bcr/abl transcripts by polymerase chain reaction (PCR). In seven out of 10 patients with chronic phase CML, BPC were Ph-negative and in 5 PCR negative. In both accelerated phase patients, BPC were Ph-negative but PCR-positive and in eight out of 28 blastic CML patients, BPC were Ph-negative and in two cases also PCR-negative. Six out of 9 ALL patients, lost the cytogenic translocations. After complete recovery, 16 patients were subsequently given high-dose therapy followed by reinfusion of 'normal' BPC.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Mobilization of cytogenetically 'normal' blood progenitors cells by intensive conventional chemotherapy for chronic myeloid and acute lymphoblastic leukemia. 810 54

Ph+ chronic myelogenous leukemia (CML) is associated with the reciprocal translocation between chromosomes 9 and 22 culminating in the production of the chimeric p210bcr/abl protein possessing elevated protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Our recent studies have revealed subtle differences in the growth, phenotypic and morphologic characteristics of subpopulations of primary lin- Ph+ chronic phase CML blasts and comparable primary normal blasts. In an attempt to correlate these biologic abnormalities and the presence of the p210bcr/abl protein, we initiated studies to identify differences in proteins constitutively phosphorylated on tyrosine in whole cell lysates of comparable primary early blast subpopulations derived from normal and Ph+ chronic phase CML marrows. Immunoblotting with anti-P-tyr Abs demonstrated a prominent 62 kDa phosphotyrosyl protein (pp62) constitutively present in 11/11 Ph+ chronic phase linblasts while being virtually undetectable in equivalent amounts of protein derived from 15/15 and 2/2 comparable normal and Ph-negative chronic phase blast populations, respectively. Immunoblotting with an Ab reportedly specific for the ras GTPase activating protein (GAP) associated p62 protein revealed that the pp62 present in CML blasts is not immunologically related to the former protein. Although the identity of the pp62 is presently not known, its prominent presence in chronic phase CML blasts, in which the only known molecular abnormality is putatively the p210bcr/abl protein, strongly suggests that it may be a critical p210bcr/abl substrate involved in an early stage of expansion of the Ph+ clone.
 ...
PMID:A 62-kilodalton tyrosine phosphoprotein constitutively present in primary chronic phase chronic myelogenous leukemia enriched lineage negative blast populations. 815 67

Decreased neutrophil alkaline phosphatase (NAP) synthesis is a classical feature of Philadelphia (Ph) positive chronic phase chronic myeloid leukemia (CML). Whether this aberration is an integral leukemic property of the cell or results from mediation by other factors is unclear. During alpha-interferon (alpha-IFN) based therapy the relationship between Ph chromosome suppression and NAP synthesis was examined. Four categories of response were observed in 19 patients studied sequentially. Significantly, persistent low NAP activity was observed in one patient in complete cytogenetic remission, while a second group of 7 patients demonstrated normal NAP activity in spite of persistence of the Ph chromosome in 100% of metaphases. In the absence of various clinical influences that can modulate NAP activity in chronic phase CML, the results reinforce the observation that the BCR/ABL fusion gene product is not a key factor influencing NAP activity in CML.
 ...
PMID:Discordant neutrophil alkaline phosphatase activity and cytogenetic response in chronic myeloid leukemia treated with alpha-interferon. 816

This study focuses on possible functional defects of circulating mature neutrophils in chronic phase chronic myelogenous leukemia (CML) and their modulation by interferon-alpha (IFN-alpha). Polymorphonuclear cells (PMN) of seven untreated and nine IFN-alpha-treated patients were evaluated for the following parameters by the following methods: generation of oxygen species, by luminol-dependent chemiluminescence; leukotriene B4 (LTB4) generation, by high-performance liquid chromatography (HPLC); expression of LTB4 and formylmethionyl-leucyl phenylalanine (FMLP) receptor sites, by 3H-binding assay; and GTPase activity, by 32P-gamma-GTP. Compared to normal controls, reduced values were obtained in treated and untreated CML for most parameters studied. Therapy with IFN-alpha resulted in significantly diminished values for oxygen species (NaF stimulation) and LTB4 (FMLP stimulation) generation, as well as FMLP receptor expression as compared to untreated CML. We conclude that alterations at the level of oxygen species production, mediator generation, receptor expression, and transmembrane signaling are involved in functional defects of circulating mature neutrophils from CML patients. IFN-alpha seems to enhance some of these functional defects, but the clinical relevance of these findings has be elucidated.
 ...
PMID:Philadelphia chromosome-positive chronic myelogenous leukemia: functional defects in circulating mature neutrophils of untreated and interferon-alpha-treated patients. 817 73

Nine patients with prolonged (> 2 years) chronic phase chronic myeloid leukaemia (CML) were investigated for the presence of T-cell involvement in the leukemic clone. Pure populations of peripheral blood T-cell populations were obtained by culturing separated mononuclear cells in the presence of pokeweed mitogen and IL2, until cultures showed > 99% pure T-cells. Purified T-cells and bone marrow and peripheral blood hematopoietic precursors were analysed for the presence of bcr-abl mRNA transcripts following RNA extraction and message amplification using polymerase chain reaction. In none of the 9 patients was bcr-abl mRNA found in T-lymphocytes while in all cases such transcripts were found in bone marrow and peripheral blood hematopoietic cells. Failure to detect T-cell involvement in patients with prolonged chronic phase CML using techniques designed to enhance even low level involvement of these cell populations supports the view that acquisition of the Ph chromosome abnormality does not occur in the totipotent stem cells but in more committed precursor cell/s with multilineage capacity but which only rarely retain the capacity for T-cell differentiation.
 ...
PMID:Lack of involvement of T-lymphocytes in the leukaemic population during prolonged chronic phase of Philadelphia chromosome positive chronic myeloid leukaemia. 822 Jan 20

Chronic myeloid leukemia (CML) has long served as a prototype malignancy for basic as well as clinical studies aimed at developing curative cancer treatment protocols. Well established features of chronic phase CML are its origin in a pluripotent stem cell, a now well defined molecular genetic basis involving the creation of a BCR-ABL fusion gene and evidence of resultant abnormalities in the mechanisms that normally control primitive hemopoietic cell proliferation. We have recently shown how the long-term marrow culture system can be adapted to quantitate and characterize a very primitive cell type in normal blood and marrow samples, as well as their normal and leukemic counterparts in patients with CML. This system has also been used to dissect mechanisms of normal progenitor regulation and to identify specific anomalies affecting leukemic (CML) progenitors. Our studies show that cells detected by their ability to initiate long-term cultures (LTC) of leukemic cells (i.e., CML LTC-initiating cells or LTC-IC) are differently distributed between marrow and blood by comparison to LTC-IC in normal individuals and, although functionally similar in terms of the number and differentiation types of clonogenic cells they produce, CML LTC-IC exhibit defective self-maintenance. Phenotypically these primitive leukemic cells are heterogeneous; the majority display features of activated/proliferating cells but a significant proportion do not. We have also documented heterogeneity in primitive CML cell responses to two factors that specifically and reversibly arrest the cycling of primitive normal hemopoietic cells; i.e., TGF-beta and MIP-1 alpha, to which CML cells are normally responsive and abnormally unresponsive, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The biology of normal and neoplastic stem cells in CML. 825 4


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