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

Histological examination of bone marrow biopsies shows that about one-third of chronic myeloid leukaemia (CML) patients exhibit an increase of megakaryocytes. The megakaryocytic predominance may be so striking that differentiation from other chronic myeloproliferative disorders (CMPD) may be difficult in some CML patients. Megakaryocytes in CML are clonal as demonstrated by loss of glucose-6-phosphate dehydrogenase isoenzymes. The Ph translocation, fusing the abl and bcr genes on chromosomes 9 and 22, however, obviously occurs as a second step in tumour development. So far, the Ph translocation has not been assigned explicitly to megakaryocytes. The question is whether the megakaryocytic cell lineage could harbour the bcr/abl fusion in those CML cases with striking proliferation of megakaryocytes but lack this genetic defect in cases with normal or decreased megakaryocyte counts. We therefore performed triple-colour fluorescence in situ hybridization (FISH) for portions of the bcr and abl genes flanking the breakpoint in CML in paraffin sections of CML cases with normal and with increased numbers of megakaryocytes. This method allows identification of the bcr/abl fusion in single, morphologically intact cells, whereas conventional cytogenetics requires lysis and thus destruction of the cell. Among the 21 CML patients examined by FISH, 10 were informative for bcr and abl genes and displayed distinct hybridization signals within nuclei of bone marrow cells. Besides the granulopoietic cells, megakaryocytes of all those patients (4 without and 6 with varying grades of megakaryocytic increase) displayed bcr/abl fusion signals indicative of a Ph translocation. The lack of hybridization signals in the remaining 11 cases indicates that this technique is not of value diagnostically and should be reserved for scientific questions. Positive controls consisted of conventional chromosome preparations from bone marrow aspirates demonstrating the Ph chromosome in all patients examined, and negative controls of paraffin sections of bone marrow biopsies from non-CML patients. These showed no fusion signals in bone marrow cells, including megakaryocytes, using FISH. Our results demonstrate clearly that not only the transforming event but also the Ph translocation leading to the bcr/abl fusion happens prior to the differentiation of the pluripotent stem cell into different myeloid lineages. The megakaryocytic proliferation evident in some CML cases is probably a consequence of the disease progress.
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PMID:Megakaryocytes carry the fused bcr-abl gene in chronic myeloid leukaemia: a fluorescence in situ hybridization analysis from bone marrow biopsies. 860 66

The Vav protooncogene is expressed almost exclusively in hematopoietic cells, but its role in regulating adult human hematopoietic cell development remains uncertain. To analyze Vav function in adult blood cell formation, we used antisense (AS) oligodeoxynucleotides (ODN) to disrupt its expression in normal and malignant human hematopoietic cells. Bone marrow or peripheral blood mononuclear cells (MNC) were obtained from consenting normal donors and patients with acute or chronic myelogenous leukemia (AML and CML, respectively) and polycythemia vera (PV). Adherent and T-cell-depleted (A-T-) MNC or CD34+ MNC were exposed to unmodified sense, antisense, or scrambled sequence ODN corresponding to codons 2-7 of Vav's mRNA sequence. Cells were then assayed for Vav mRNA expression by reverse transcription-polymerase chain reaction and Vav protein expression by Western binding. After showing that Vav-targeted AS ODN could specifically diminish Vav mRNA and protein expression, we assessed the ability of Vav-deficient cells to form myeloid and erythroid colonies in methyl-cellulose cultures. When normal CD34+ MNC were exposed to Vav AS ODN, no effect on colony-forming unit-granulocyte-macrophage (CFU-GM) or CFU-megakaryocyte colony formation was observed. In contrast erythroid colony growth was inhibited by a mean +/- SD of 62% +/- 16%. In patients with hematopoietic malignancies. Vav-targeted AS ODN inhibited CFU-GM colony formation in a sequence-specific and dose-dependent manner in 1 of 3 AML, 13 of 17 CML, and 2 of 2 PV patients. At the highest concentration used, the Vav AS ODN inhibited CFU-GM colony formation from 66% to 81% when compared with control cell colony growth. Burst-forming unit-erythroid (BFU-E) colony-formation was also assessed in 7 PV patients. The Vav-targeted AS ODN inhibited BFU-E colony formation in all by a mean +/- SD of 81% +/- 4%. These findings suggest that Vav function may not be easily complemented in a significant subset of normal adult erythroid progenitor cells and may also be necessary for myeloid progenitor cell growth in a variety of hematopoietic malignancies.
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PMID:A functional analysis of protooncogene Vav's role in adult human hematopoiesis. 860 21

Thrombopoietin stimulated blast colony formation in 11/20 acute myelogenous leukaemia (AML) patients studied. The FAB subtypes of the blasts responding to thrombopoietin were not restricted to those of the megakaryocyte lineage, but also included M1-M5 AML blasts. The morphology of colony cells produced by megakaryocytic blasts showed megakaryocytoid features, whereas colony cells produced by M1-M5 AML blasts remained myeloblasts. An increase in CD41 was observed in the cells of colonies produced by blasts from the megakaryocyte lineage involving leukaemia and chronic myeloid leukaemia in blastic crisis. Thrombopoietin receptor was observed on leukaemic blasts which formed colonies following incubation with thrombopoietin.
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PMID:Growth stimulatory effect of thrombopoietin on the blast cells of acute myelogenous leukaemia. 879 Jan 52

To assess possible alterations of megakaryocytes associated with interferon (IFN) and busulfan (BU) therapy of Ph(1+)-CML, an immunohistochemical and morphometric study was performed on trephine biopsies of the bone marrow taken before and at varying intervals during treatment. For the identification of megakaryopoiesis and its endoreduplicative activity the monoclonal antibodies CD61 (anti-platelet glycoprotein IIIa) and PC10 raised against proliferating cell nuclear antigen (PCNA) were used. We compared 60 specimens from 20 patients following IFN alpha-2b administration (in combination with IFN gamma in seven patients) with 57 specimens from 22 patients after monotherapy with BU. A close correlation with clinical follow-up studies revealed that in the IFN-treated group the prevalence of atypical micro-megakaryocytes, usually characterizing CML, was conspicuously reduced in repeatedly taken bone marrow samples. Initially, even an increase in size which was levelled to normal values during maintenance therapy was observed. These features were most prominently expressed in the 13 patients with a complete hematologic and/or partial cytogenetic response. Associated with this phenomenon was a significant enhancement of the PCNA-labelling index which indicated a stimulation of endoreduplicative (endomitotic) activity necessary for achieving normal size and ploidy. In the second group of patients treated by BU these changes were absent. For this reason, our findings are in keeping with the assumption that during IFN treatment, there is at least partial recovery and expansion of a putative normal (Ph1-) megakaryopoiesis. In conclusion, megakaryocyte morphology, i.e. normalization in size, is thought to be a useful indicator to evaluate the response to IFN in CML patients.
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PMID:Interferon therapy, but not busulfan restores normal-sized megakaryopoiesis in CML--a comparative histo- and immunomorphometric study. 884 3

Megakaryocyte proliferation in bone marrow is a feature common to the three Philadelphia negative chromosome myeloproliferative disorders (MPD)--essential thrombocythemia (ET), polycythemia vera, and myelofibrosis with splenic myeloid metaplasia--and chronic myelocytic leukemia. Enlarged megakaryocytes, clustering in close neighbouring with multilobulated nuclei are the hallmark of all the Philadelphia negative chromosome MPD. Clonality of hematopoietic cells, based on X-chromosome inactivation can now be studied in a majority of female patients in all nucleated cell fractions as well as in platelets. A significant increase in circulating CFU-MK has been repeatedly observed in MPD as well as a spontaneous megakaryocyte colony formation in a majority of ET patients. Hypersensitivity to thrombopoietin (TPO) in relation with a functional defect of the TPO-MPL pathway may play a major role in spontaneous megakaryocyte growth. There is presently no currently available test of platelet functions able to predict the risk of occurrence of thrombotic or haemorrhagic complications in MPD patients. However the role of platelets activation in the pathogenesis of ischemic erythromelalgia has been established.
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PMID:[Dysmegakaryocytopoiesis and dysthrombopoiesis in myeloproliferative syndromes]. 907 18

In this report an attempt has been made to discuss some of the issues pertinent to myelofibrosis complicating chronic myeloproliferative disorders (CMPDs) that are significantly associated with megakaryocyte function. In this context, biochemical, clinical and particularly morphological features were reviewed. Morphological findings based on elaborate techniques were in keeping with the assumption that in chronic myeloid leukemia (1) the number of CD61-positive megakaryocytes, and in particular their precursors were the parameters most closely associated with myelofibrosis (2) an increased content of reticulin fibers in follow-up biopsies significantly correlated with laboratory data indicative of a high tumor burden (anemia, peripheral blasts, hepatosplenomegaly) and thus a more advanced stage of the disease process (3) even a slight increase in reticulin, i.e. doubling of the normal fiber density was associated with a worse prognosis independent of therapeutic regimens given (4) Dynamics of myelofibrosis was significantly influenced by treatment. In this context, calculation of the myelofibrosis progression index (MPI) revealed a higher score following interferon therapy compared with busulfan. In addition, in idiopathic myelofibrosis (5) the evolution of myelofibrosis was unpredictable and according to the MPI, progression occurred at a relatively low rate (6) proliferation and dilatation of sinusoids accompanying intravascular hematopoiesis and collagen type IV deposits were predominant features in later (fibro-osteosclerotic) stages in the course of disease (7) transmural migration of megakaryocytes demonstrated by three dimensional reconstruction revealed a mole-like tunneling through the thickened sinusoidal wall. A very careful assessment of the numerous correlations between bone marrow features and laboratory data will allow clinicians and pathologists to gain a better insight into the mutual relationships between hematological and morphological findings in CMPDs.
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PMID:Clinicopathological impact of the interaction between megakaryocytes and myeloid stroma in chronic myeloproliferative disorders: a concise update. 908 37

Identification of megakaryocytes by immunohistochemistry may be superior to hematoxylin-eosin (HE) stain method for assessing megakaryocyte size and number in clinical specimens; however, a side-by-side comparison of the two methods has not been reported. In the present study, comparative morphometry using both methods was performed on marrow biopsies of normal individuals, and of patients with myelodysplastic syndrome, chronic myeloid leukemia and immune thrombocytopenia. Morphometric results in the present study showed that precise megakaryocyte size can be calculated in normal and pathologic bone marrow sections by using HE stain if one employs stereological corrections. In contrast, megakaryocyte numbers can be more precisely detected by immunohistochemistry than by HE stain, particularly in myelodysplastic syndrome and chronic myeloid leukemia. Differentiation disturbances and ineffective megakaryocytopoiesis in myelodysplastic syndrome were demonstrated by immunomorphometric analyses.
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PMID:Comparative morphometric study of immunohistochemical versus conventional staining for the evaluation of megakaryocytopoiesis in normal and pathological bone marrow biopsies. 914 25

We have identified ten patients with acute myeloid leukemia (AML) and one patient with chronic myeloid leukemia with megakaryocytic crisis who displayed an inv(3)(q21q26). Seven of them had an additional monosomy 7. Most of them had a myelodysplastic syndrome (MDS) preceding AML, normal or increased platelet counts, increased number of megakaryocyte, megakaryocytic dysplasia, and erythroid dysplasia. There was a high incidence of resistance to induction chemotherapy, short remission time, and early relapse. Seven patients were immunologically analyzed. The main immunophenotypes were as follow: CD7+, CD34+, HLA-DR+, CD38+, CD13+, CD33+, CDw65+, CD2-, CD3-, CD4-, CD8-, CD19+, CD20-, CD11b-. Our results suggest that the leukemia with inv(3)(q21q26) represents a new cytogenetic-clinicopathologic subtype, characterized by 1) abnormal megakaryopoiesis and multiple hematopoietic lineage involvement; 2) an antecedent MDS; 3) poor response to conventional chemotherapy; and 4) expression of CD7, CD34, CD38, HLA-DR, CD13, and CD33 antigens. We propose that the malignant transformation in patients with inv(3)(q21q26) occurs in an early stem cell prior to lineage commitment.
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PMID:Chromosomal abnormality inv(3)(q21q26) associated with multilineage hematopoietic progenitor cells in hematopoietic malignancies. 920 72

To elucidate the effects of interferon-alpha (IFN-alpha) on normal human bone marrow in vivo, an immunomorphometric study was performed using trephine biopsy specimens without hematopoietic pathology. Samples were derived from patients with mycosis fungoides but no marrow involvement, who were undergoing low-dose IFN-alpha treatment. Parameters included density of reticulin (argyrophilic) fibers, CD61+ megakaryocytes, PGM1+ macrophages, the GSA-I lectin-expressing (activated) macrophage subpopulation, proliferative activity (PCNA staining), and apoptosis. Following IFN-alpha therapy (3 x 3 x 10(6) U/week between 6 and 21 months), morphometric evaluation of sequential bone marrow examinations revealed a significant increase in the number of megakaryocytes and the amount of reticulin fibers. Additionally, there was an overall decrease in PCNA+ cells, accompanied by a reduction in the incidence of apoptotic bodies. On the other hand, total number of macrophages and their activated subfraction remained unchanged. Opposed to in vitro findings, a fibrogenetic capacity of IFN-alpha associated with megakaryocyte growth was detectable. Moreover, contrasting with effects of IFN-alpha treatment in chronic myelogenous leukemia, the incidence of apoptosis was significantly reduced. This feature was assumed to contribute to a maintenance of steady-state hematopoiesis expressed by a nonaltered bone marrow cellularity in our specimens.
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PMID:Effect of IFN-alpha on normal human hematopoiesis: an immunohistochemical and morphometric study on trephine biopsy specimens. 956 27

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of anagrelide are reviewed. Anagrelide is a selective thrombocytopenic agent with FDA-approved labeling for the treatment of essential thrombocythemia. Clinical trials have shown that the drug may have a role in the treatment of other chronic myeloproliferative disorders, including polycythemia vera, chronic myeloid leukemia, and agnogenic myeloid metaplasia. The mechanism by which anagrelide reduces platelet count is not yet clear. The current hypothesis is that anagrelide affects the late (postmitotic) phases of megakaryocyte development. Anagrelide has a large volume of distribution and is extensively metabolized; less than 1% is recovered unchanged in the urine. Plasma half-life after a 0.5-mg dose is 1.3 hours. Anagrelide's efficacy and safety have been evaluated in open-label, noncomparative trials, in which the response rate was 60-93%. Adverse effects include headache, diarrhea, edema, palpitations, and abdominal pain. Patients with renal or hepatic dysfunction need to be closely monitored for signs of toxicity. The recommended starting dosage is 0.5 mg four times a day or 1 mg twice a day, with dosage adjustment to the lowest effective amount required to reduce and maintain platelet count below 600 x 10(9)/L. The wholesale acquisition price for 0.5-mg capsules is $350 per 100. Whether anagrelide will replace hydroxyurea as first-line therapy in some or all patients remains to be determined. Anagrelide is effective in the treatment of essential thrombocythemia and may have a role in the treatment of other myeloproliferative disorders.
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PMID:Anagrelide, a selective thrombocytopenic agent. 978 84


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