NORMAL LIPOXYGENASE ACTIVITY IN ERYTHROMELALGIC THROMBOTIC THROMBOCYTHEMI

1987 ◽  
Author(s):  
J J Michiels ◽  
E Haddeman
Keyword(s):  
Bone Marrow ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Myeloproliferative Disorders ◽  
Lipoxygenase Activity ◽  
Chromosome 9 ◽  
Eicosatetraenoic Acid ◽  
Myeloproliferative Disease ◽  
Giant Platelets ◽  
Myeloid Metaplasia

It has been suggested that a selective lipoxygenase deficiency may be a mechanism for hyperfunction of platelets in myeloproliferative disorders. 24 out of 60 patients with one of the myeloproliferative disorders polycythemia vera, myeloid metaplasia and myelofibrosis, essential thrombo-cythemia or chronic myeloid leukemia have been reported to be deficient for platelet lipoxygenase activity (NEJM 1982; 306:381). These patients paradoxically tended to have a greater hemorrhagic tendency rather than thrombotic episodes. We investigated platelet lipoxygenase activity in clearly defined patients with erythromelalgic, thrombotic thrombocythemia (til) (Ann IntMed 1985; 102:466) while on treatment with low dose aspirin in order to prevent platelet activation in vivo or in vitro. The production of hydroxyheptodecatrienoic acid (HHT) by cyclo-oxygenase and 12-hydroxy-eicosatetraenoic acid (12-HETE) by lipoxygenase in 14C labeled platelets after stimulation with thrombin or arachidonic acid were estimated in 12 ETT patients and in 3 patients with reactive thrombocytosis (RT). HHT and 12-HETE were measured with the technique of High Performance Liquid Chromatography. Platelet lipoxygenase activity was completely normal in the 3 patients with RT and in 9 of 12 patients with ETT. Three ETT patients were severely deficient for platelet lipoxygenase activity. Two of them had progressive myeloproliferative disease with very high platelet counts, many large and some giant platelets, a few megakaryoblasts and chromosomal abnormalities of bone marrow cells (trisomy of chromosome 9 and 18p+, 1P-, 11a- respectively). Normal bone marrow karyograms were found in the 9 ETT patients with normal platelet lipoxygenase activity and stable disease. In conclusion platelet lipoxygenase deficiency is not a feature of ETT, but may reflect abnormal megakaryopoesis in progressive myeolo-proliferative disorders.

Hemostatic Disorders and Platelet Nucleotide Release in Myeloproliferative Disease

1979 ◽  
Author(s):  
A.B. Hagedorn ◽  
E.J.W. Bowie ◽  
C.A. Owen
Keyword(s):  
Platelet Aggregation ◽  
Postoperative Bleeding ◽  
Myeloproliferative Disorders ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Normal Platelet ◽  
Agnogenic Myeloid Metaplasia ◽  
Nucleotide Release ◽  
The One ◽  
Hemostatic Disorders

Since patients with myeloproliferative disorders may have bleeding tendencies, the surgeon, in particular, is anxious for an hemostatic evaluation if splenectomy is contemplated. It is known that platelet aggregation, particularly with epinephrine, tends to be reduced in these patients. The nucleotide content of their platelets may be deficient. Furthermore, megakaryocytic fine structure is often abnormal. We have studied, In detail, 9 patients with hemostatic disorders. Diagnoses included polycythemia vera, agnogenic myeloid metaplasia, evolving myeloproliferative disease and erythroleukemia. Ages ranged from 36 to 75 years. Bleeding tendencies, including bruising, operative or postoperative bleeding, melena, hematuria, and hemarthrosis, characterized 8 of the 9 patients; the one exception had normal platelet ADP and elevated ATP. All had abnormal platelet aggregation, but the extent of the abnormality could not be related to the ADP and ATP contents of the platelet.ADP (normal 26.7 ± 6.5 nmol/109 platelets) was reduced in 7. ATP (normal 38.6 ± 7.6 nmol/109 platelets) was reduced in 1, elevated in 2 and normal in the other 6. In no patient were both values normal. Nucleotide release induced by collagen activation was measured in 6 of the patients. In all 6 it was deficient whether platelet ADP were normal (1 case) or depressed (5) and whether platelet ADP were elevated (1) or decreased (3).

scholarly journals Group-C Trisomy in Myeloid Metaplasia with Possible Leukemia

Blood ◽  
1964 ◽  
Vol 24 (6) ◽  
pp. 716-725 ◽  
Author(s):  
AVERY A. SANDBERG ◽  
TAKAAKI ISHIHARA ◽  
LOIS H. CROSSWHITE
Keyword(s):  
Bone Marrow ◽  
Blood Culture ◽  
Acute Leukemia ◽  
Chromosomal Abnormality ◽  
Blood Cells ◽  
Karyotype Analysis ◽  
Myeloproliferative Disorders ◽  
Normal Female ◽  
Myeloid Metaplasia ◽  
Definite Relationship

Abstract A chromosomal abnormality in marrow and blood cells has been found in only one patient out of a group of 20 subjects with myeloproliferative disorders other than leukemia. The abnormal karyotypic finding consisted of group C9 trisomy in a patient with myeloid metaplasia and an acute leukemia-like picture and indicates a definite relationship to acute leukemia. The latter has been shown to be not infrequently accompanied by C9 trisomy. The trisomy was accompanied by the presence of a substantial number of hypertetraploid cells in the marrow but not in the cultured blood cells. As a matter of fact, the blood culture yielded predominantly metaphases with 47 chromosomes (C9 trisomy) on the first examination and metaphases with 46 chromosomes and a normal female karyotype on the second occasion. The superiority of bone marrow karyotype analysis over that of blood cells in leukemic states is thus indicated.

scholarly journals Detection by enzymatic amplification of bcr-abl mRNA in peripheral blood and bone marrow cells of patients with chronic myelogenous leukemia

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1735-1741 ◽  
Author(s):  
W Lange ◽  
DS Snyder ◽  
R Castro ◽  
JJ Rossi ◽  
KG Blume
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Bone Marrow Cells ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Enzymatic Amplification ◽  
Polymerase Chain ◽  
Marrow Cells

Abstract The Philadelphia chromosome of chronic myelogenous leukemia (CML) patients is caused by a translocation of the c-abl gene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22. A new bcr- abl mRNA is expressed in these cases. We have developed a modified polymerase chain reaction (PCR) for the detection of this mRNA. The method is extremely sensitive, reliable, and relatively fast. The analysis of peripheral blood or bone marrow cells from CML patients treated with chemotherapy shows that the two possible mRNAs are expressed in various combinations. Our results show that even after myeloablative therapy for bone marrow transplantation bcr-abl mRNAs are still expressed. Further studies, however, are necessary to determine the clinical relevance of a small number of persisting cells expressing the bcr-abl mRNA.

Loss of the Y Chromosome from Bone Marrow Cells of Males with Myeloproliferative Disorders

1977 ◽  
Vol 57 (5) ◽  
pp. 310-320 ◽  
Author(s):  
P.E. DiLeo ◽  
H. Müller ◽  
J.-P. Obrecht ◽  
B. Speck ◽  
E.M. Bühler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Y Chromosome ◽  
Bone Marrow Cells ◽  
Myeloproliferative Disorders ◽  
Marrow Cells

scholarly journals Increased circulating neutrophils with surface receptor activity for immunoglobulin G in polycythemia vera and myeloid metaplasia

Blood ◽  
1979 ◽  
Vol 53 (6) ◽  
pp. 1106-1113 ◽  
Author(s):  
HS Gilbert ◽  
R Goldberg ◽  
L Ward
Keyword(s):  
Polycythemia Vera ◽  
High Titer ◽  
Myeloproliferative Disorders ◽  
Normal Subjects ◽  
Receptor Activity ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Activated State ◽  
Surface Receptor ◽  
Igg Receptors

Abstract Reports of heterogeneity of IgG receptor activity of normal circulating neutrophils prompted measurements in myeloproliferative disease to determine if dysplasia of the hematic stem cell resulted in an abnormality of this membrane property. IgG receptors were assayed by rosette formation in suspension with human Rh-positive erythrocytes sensitized with high-titer Rh antiserum. IgG receptors were detected on 19 +/- 1.6% (mean +/- SEM) of neutrophils from 45 normal subjects. A significant increase in IgG-receptor-bearing neutrophils was found in polycythemia vera (PV) and myeloid metaplasia (MyM), with values of 70 +/- 3.6% and 69.7 +/- 4.3%, respectively. Normal values were observed in polycythemic states not due to myeloproliferative disease and in chronic myelocytic leukemia. Rosette-forming neutrophils were increased to 52.3 +/- 3.7% in infection and inflammatory disease, but this value was significantly lower than those in PV and MyM. Increased IgG receptors in PV and MyM may be related to the activated state of the neutrophil and may result from an intrinsic cellular abnormality of the proliferating clone or from altered bone marrow release. Quantitation of neutrophil IgG receptors may be of value in the differential diagnosis of PV and MyM and may offer insights into the derangement of hematopoiesis that underlies these myeloproliferative disorders.

scholarly journals Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 368-379 ◽  
Author(s):  
Jinyong Wang ◽  
Yangang Liu ◽  
Zeyang Li ◽  
Zhongde Wang ◽  
Li Xuan Tan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Marrow Transplant ◽  
Dependent Manner ◽  
Myeloproliferative Disease ◽  
Cell Type ◽  
Nras Mutation ◽  
Secretase Inhibitor ◽  
Marrow Cells

Abstract Both monoallelic and biallelic oncogenic NRAS mutations are identified in human leukemias, suggesting a dose-dependent role of oncogenic NRAS in leukemogenesis. Here, we use a hypomorphic oncogenic Nras allele and a normal oncogenic Nras allele (Nras G12Dhypo and Nras G12D, respectively) to create a gene dose gradient ranging from 25% to 200% of endogenous Nras G12D/+. Mice expressing Nras G12Dhypo/G12Dhypo develop normally and are tumor-free, whereas early embryonic expression of Nras G12D/+ is lethal. Somatic expression of Nras G12D/G12D but not Nras G12D/+ leads to hyperactivation of ERK, excessive proliferation of myeloid progenitors, and consequently an acute myeloproliferative disease. Using a bone marrow transplant model, we previously showed that ∼ 95% of animals receiving Nras G12D/+ bone marrow cells develop chronic myelomonocytic leukemia (CMML), while ∼ 8% of recipients develop acute T-cell lymphoblastic leukemia/lymphoma [TALL] (TALL-het). Here we demonstrate that 100% of recipients transplanted with Nras G12D/G12D bone marrow cells develop TALL (TALL-homo). Although both TALL-het and -homo tumors acquire Notch1 mutations and are sensitive to a γ-secretase inhibitor, endogenous Nras G12D/+ signaling promotes TALL through distinct genetic mechanism(s) from Nras G12D/G12D. Our data indicate that the tumor transformation potential of endogenous oncogenic Nras is both dose- and cell type-dependent.

scholarly journals Transplantable myeloproliferative disease induced in mice by an interleukin 6 retrovirus.

1992 ◽  
Vol 176 (4) ◽  
pp. 1149-1163 ◽  
Author(s):  
R G Hawley ◽  
A Z Fong ◽  
B F Burns ◽  
T S Hawley
Keyword(s):  
Bone Marrow ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Bone Marrow Cells ◽  
Constitutive Expression ◽  
Fold Increase ◽  
Neutrophil Infiltration ◽  
Microcytic Anemia ◽  
Myeloproliferative Disease

Lethally irradiated mice transplanted with bone marrow cells infected with a novel recombinant retrovirus (murine stem cell virus-interleukin 6 [MSCV-IL-6]) bearing a mouse IL-6 gene developed a fatal myeloproliferative disease within 4 wk of engraftment. The hematologic manifestations of the syndrome included elevated peripheral leukocyte counts (up to 430 x 10(3) cells/mm3) with a predominance of neutrophilic granulocytes, microcytic anemia, and thrombocytosis or thrombocytopenia. The mice showed extensive neutrophil infiltration of the lungs, liver, and occasionally lymph nodes, plus splenomegaly resulting from enhanced splenic myelopoiesis (30-60-fold increase in progenitor numbers). Despite the chronic stimulation of neutrophil excess by IL-6, bone marrow from affected mice was capable of repopulating the hematopoietic tissues (bone marrow and spleen) of lethally irradiated hosts during repeated serial transplantation. In the longest documented case, the progeny of a single MSCV-IL-6-marked cell transferred the myeloproliferative disease to two secondary, four tertiary, and two quaternary recipients (the clone endured for a total of 72 wk). These results, demonstrating considerable proliferative longevity of the IL-6-producing cells, support an in vivo role of IL-6 in the maintenance of hematopoietic precursors. Dysregulated IL-6 production also had significant systemic effects. The mice displayed increased mesangial cell proliferation in the kidney, frequent liver abnormalities, and marked alterations in plasma protein levels. Unlike previous studies where constitutive expression of exogenous IL-6 genes resulted in lymphoproliferative disorders characterized by massive plasmacytosis, minimal plasma cell expansion occurred in the MSCV-IL-6 mice during the observation period. Potential explanations for the differences in disease phenotypes observed in the present and previous studies are different cell types expressing the exogenous IL-6 genes, higher sustained circulating levels of IL-6 achieved using the MSCV-IL-6 retroviral delivery system, and/or the premature death (3-15 wk after transplantation) of the MSCV-IL-6 mice before the onset of plasmacytosis. This animal model should prove useful for further investigation of the function of IL-6 in normal and abnormal hematopoiesis and in inflammatory responses.

Chromosomal Abnormalities in MDS Are Linked to Dysregulation of CDC20 and CEP55 Genes

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Mayara Magna de Lima Melo ◽  
Daniela de Paula Borges ◽  
Antônio Wesley Araújo Dos Santos ◽  
Gabrielle Melo Cavalcante ◽  
Leticia Rodrigues Sampaio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Mitotic Arrest ◽  
Complex Karyotype ◽  
Increased Risk

Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by cytopenias and an increased risk of progression to acute myeloid leukemia (AML). Its pathogenesis is strictly linked to chromosomal instability, which in turn provides a valuable prognostic marker. Malignant cells develop alternative routes to escape mitosis checkpoints, overcoming the mitotic arrest imposed by Spindle Assembly Checkpoint (SAC), a process dependent on CDC20 inactivation. Abnormal levels of CDC20 can inhibit mitotic arrest, promoting premature exit from mitosis. Overexpression of CEP55 also facilitates the mitotic exit, resulting in polyploidy (an event called Mitotic Slippage). Since chromosomal abnormalities are one of the most important prognostic factors for patients with MDS, this study aimed to analyze the possible link between chromosomal abnormalities and CDC20 and CEP55 mRNA expression in MDS. We evaluated the bone marrow cells from 45 patients diagnosed as MDS according to 2016 WHO-classification (1 MDS-SLD, 15 MDS-RS-MLD, 5 MDS-MLD, 1 t-MDS, and 23 MDS-EB) and 5 bone marrow of healthy controls. Conventional Karyotyping was performed by G-banding of 20 metaphases whenever possible. TaqMan expression assays for CDC20 (Hs00426680_mH) and CEP55 (Hs01070181_m1) were performed in duplicate and the expression ratios were calculated using the 2−ΔCq method. Normality was evaluated by Shapiro-Wilk test. Outliers were removed. The Student's t-test or one-way ANOVA with Tukey/Games Howell post-hoc test was used to analyze the influence of relative expression regarding variables. Patients with MDS showed increased expression of CDC20 and CEP55 compared to healthy individuals (p<0.0001 and p<0.0001). Regarding karyotype, there was the overexpression of CDC20 and CEP55 in patients with altered karyotype and aneuploid karyotype when compared to patients with normal karyotype (p <0.0001 and p =0.001; p = 0.013 and p = 0.022, respectively) (Figure 1A-D). CDC20 and CEP55 have fundamental functions in controlling the progression of metaphase to anaphase and both, when upregulated, induce chromosomal instability. Additionally, patients with del(7q) and complex karyotype showed hyperexpression of CEP55 when compared with patients with normal karyotype (p = 0.005 and p = 0.019) (Figure 1E-F), while patients with deletion (5q) had an increased expression of CDC20 when compared with patients with normal karyotype (p <0.0001). Our group previously demonstrate that high CDC20 protein expression is associated with complex karyotype in MDS patients. Thus, we hypothesized that the deregulation of CDC20 and CEP55 expression induces chromosomal changes, each one in its way. Both can cause disturbances in crucial phases of mitosis (anaphase and cytokinesis, respectively). Finally, we detected a strong correlation between CDC20 and CEP55 (r = 0.646; p <0.0001), suggesting both genes may play a synergistic role during chromosomal abnormalities in MDS, creating possible new targets to be evaluated in MDS. Our data suggest CDC20 and CEP55 as possible new therapeutic targets in MDS. There is a need for further studies, validations and urgent in-depth investigations in cell lines/primary samples or murine models. Disclosures No relevant conflicts of interest to declare.

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