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 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

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.

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 A Study of Histamine in Myeloproliferative Disease

Blood ◽  
1966 ◽  
Vol 28 (6) ◽  
pp. 795-806 ◽  
Author(s):  
HARRIET S. GILBERT ◽  
RICHARD R. P. WARNER ◽  
LOUIS R. WASSERMAN
Keyword(s):  
Polycythemia Vera ◽  
Clinical Manifestations ◽  
White Cell ◽  
Histamine Content ◽  
Elevated Blood ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Objective Evidence ◽  
Blood Histamine

Abstract 1. Whole blood histamine content was measured in 80 patients with myeloproliferative disease. Increased levels were found in 60 per cent of patients with uncontrolled polycythemia vera, in 7 per cent of patients with polycythemia vera being controlled by myelosuppressive therapy, and in 71 per cent of a group with "spent" polycythemia, myeloid metaplasia and myelofibrosis. 2. The excretion of histamine in the urine was measured in 60 patients, 30 with elevated blood histamine and 30 with normal blood histamine. The urine findings paralleled the blood findings in 90 per cent of the cases. 3. Measurements of cell-poor and cell-rich fractions of blood showed that the histamine is contained in the white cell fraction. Elevated basophil counts were present in 50 per cent of the patients and occurred with the greatest frequency in the groups with elevated blood and urine histamine. A rough correlation between the basophil count and the histamine content of blood and white cell fractions was observed in normal subjects and most cases with myeloproliferative disease. Data obtained in some cases of myeloproliferative disease suggest that the histamine content of the basophil may be abnormal and that other granulocytes may contribute to the total leukocyte histamine. 4. Myelosuppressive agents produced a reduction in histamine (expressed per 109 myeloid cells) and a decrease in urine histamine as control of the myeloproliferative process was achieved. Treatment with phlebotomy alone produced no change in histamine levels. 5. The incidence of pruritus, upper gastrointestinal distress and urticarial manifestations was increased 7-fold, 4-fold and 12-fold, respectively, in patients with elevated histamine levels as compared with those who had normal histamine levels. 6. Cyproheptadine, a potent antihistaminic, successfully controlled pruritus, relieved pyrosis and suppressed urticarial eruptions in patients with elevated histamine levels. Suppression of the reaction to subcutaneously administered codeine (a histamine-releaser) afforded objective evidence that cyproheptadine blocked the effects of histamine release in vivo. 7. The metabolism of histamine and the role of elevated histamine levels in the clinical manifestations and pathophysiology of myeloproliferative disease are discussed.

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.

JAK2 Inhibitors for the Treatment of Myeloprolifertive Disorders.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3632-3632 ◽  
Author(s):  
John Hood ◽  
Jon Cao ◽  
Ehab Hanna ◽  
Dan Lohse ◽  
Chi Ching Mak ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
In Vitro Assays ◽  
Single Mutation ◽  
Myeloid Metaplasia ◽  
Large Patient ◽  
Transformed Cell Lines ◽  
Jak2 Inhibitors

Abstract The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia has been conclusively linked to a single mutation in JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases. Assays in several laboratories indicate that between 90–100% of patients with polycythemia vera harbor this allele. Because the JAK2.V617F gain-of-function mutant affects such a large patient population, pharmacologically targeting the mutated JAK2 is highly clinically relevant. In order to address this unmet clinical need we designed and synthesized a series of structurally novel compounds for their capacity to inhibit JAK2.V617F. Compounds were identified which potently inhibited JAK2 enzyme, with enzymatic IC50s as low as 1 nM. Subsets of this group were subsequently identified which were highly selectivity against undesirable off-target kinases, including up to 100X selectivity versus the highly homologous JAK3 kinase. Compounds were then advanced into in vitro assays in JAK2.V617F transformed cell lines in which compounds were identified with proliferation EC50s as low as 60 nM (representative compounds listed in Table below). Compounds from this series were subsequently shown to be orally available and efficacious in rodent models of MPD driven disease. Conclusion: TargeGen has synthesized a series of JAK2.V617F inhibitors with promising potency, selectivity and pharmaceutical properties for utility in the treatment of myeloproliferative disorders. Representative JAK2 Inhibitors Compound Primary Target Selectivity Profile Cell EC50 JAK2 IC50 JAK2 vs JAK3 (X-fold selectivity) BaF3:JAK2.V617F TG101192 3.8 15 140 TG101209 6 28 279 TGs101348 12.5 83 297 JAK Inhibitor I (Calbiochem) 10 1.5 320

MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3472-3476 ◽  
Author(s):  
Animesh D. Pardanani ◽  
Ross L. Levine ◽  
Terra Lasho ◽  
Yana Pikman ◽  
Ruben A. Mesa ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
De Novo ◽  
Blast Crisis ◽  
Molecular Testing ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Mutational Frequency ◽  
Mutational Status ◽  
Myelofibrosis With Myeloid Metaplasia ◽  
Myelomonocytic Leukemia

Abstract Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

scholarly journals The effect of hydroxyurea on hemoglobin F in patients with myeloproliferative syndromes

Blood ◽  
1985 ◽  
Vol 66 (2) ◽  
pp. 373-379
Author(s):  
BP Alter ◽  
HS Gilbert
Keyword(s):  
Polycythemia Vera ◽  
Fetal Hemoglobin ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Hemoglobin F ◽  
Myeloid Metaplasia ◽  
Agnogenic Myeloid Metaplasia ◽  
Daily Dose ◽  
Almost All ◽  
Potential Use

Fetal hemoglobin (Hb F) may increase in patients receiving chemotherapeutic drugs, a result of potential use in patients with symptomatic hemoglobinopathies. We examined Hb F in 13 patients with myeloproliferative disease (six polycythemia vera, five polycythemia vera with myeloid metaplasia, one agnogenic myeloid metaplasia, and one chronic myelogenous leukemia) who were treated with hydroxyurea. Four patients showed an increase in Hb F from less than 1% to between 5% and greater than 8% while on hydroxyurea, and a decline to less than 1% when the drug was discontinued. This group of “responders” received a higher average daily dose of hydroxyurea, which was administered continuously rather than intermittently, when compared to the “nonresponders.” Mean corpuscular volumes (MCVs) rose in most patients, and i antigen remained elevated or decreased; neither parameter correlated with Hb F levels. Both responders and nonresponders had therapeutically desirable suppression of WBCs and platelets, and almost all had no depression of reticulocytes or Hb.

TG101348, a potent, highly selective JAK2 inhibitor, inhibits colony formation in stem cells from polycythemia vera patients and prevents JAK2V617F-mediated splenomegaly and death in a mouse model

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7031-7031 ◽  
Author(s):  
J. Hood ◽  
J. Doukas ◽  
M. Martin ◽  
G. Noronha ◽  
C. Jamieson ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Colony Formation ◽  
Cell Model ◽  
Myeloproliferative Disorders ◽  
Myeloid Metaplasia ◽  
Jak2 Inhibitor ◽  
Potent Inhibition ◽  
Pharmaceutical Properties ◽  
Myelofibrosis With Myeloid Metaplasia

7031 Background: The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia has been strongly linked to an activating mutation of JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino acid residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases. Methods: In order to address this unmet clinical need we designed, synthesized and performed preclinical evaluations on a series of structurally novel compounds optimized for JAK2 inhibition. Results: TG101348, a compound which potently inhibits JAK2V617F enzymatically and in human cells, was selected as a clinical development candidate from this medicinal chemistry campaign. TG101348 displays remarkable kinase specificity as shown by 83X selectivity versus JAK3 and potent inhibition of <2% of the kinases evaluated in a commercial, phylogenetically diverse panel of 212 kinases. TG101348 potently inhibits erythroid colony formation in patient-derived cells from polycythemia patients at doses 2–3X lower than in normal control patients. Consistent with this observation TG101348 inhibits JAK2-driven STAT5 phosphorylation, cell proliferation and cell survival in JAK2V617F-expressing cell lines. In vivo, TG101348 exhibits promising pharmacokinetic profiles in species ranging from mouse to monkey including oral availabilities >20%, and half-lives consistent with once or twice daily dosing. TG101348 reduces the number of circulating mutant JAK2 cells, inhibited splenomegaly and improved survival without significantly impacting normal hematocrit in an aggressive JAK2-driven circulating cell model of disease in rodents. Conclusion: TG101348 has considerable potential for the treatment of JAK2- driven myeloproliferative disorders based on its promising preclinical potency, selectivity and pharmaceutical properties. [Table: see text]

The Clinical and PRV-1 Expression Phenotype of Wild-Type, Heterozygous, and Homozygous JAK2 V617F in Polycythemia Vera.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 255-255
Author(s):  
Ayalew Tefferi ◽  
Shireen Sirhan ◽  
Terra L. Lasho ◽  
Susan M. Schwager ◽  
Jacob S. Strand ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Mutation Screening ◽  
Jak2 V617f ◽  
Transcript Level ◽  
Myeloproliferative Disorders ◽  
Dose Effect ◽  
Limited Information ◽  
Wild Type ◽  
Myeloid Metaplasia ◽  
Mutational Status

Abstract BACKGROUND. Several studies have recently reported on the occurrence of a JAK2 V617F mutation in myeloid cells from the majority of patients with polycythemia vera (PV). The clinical relevance of this novel observation is currently under study. Similarly, there is limited information regarding the correlation of JAK2 V617F mutational status and neutrophil PRV-1 transcript level in PV, secondary polycythemia (SP) and other myeloproliferative disorders (MPD). METHODS. In a single institutional study, mutation screening for JAK2 V617F was performed in DNA derived from archived blood granulocytes from 63 consecutive patients with PV in whom current diagnostic criteria were strictly applied and diagnosis confirmed by bone marrow histology. Concomitant quantitative analysis of neutrophil PRV-1 expression was performed in 28 of the 63 patients and the results of both JAK2 V617F and PRV-1 analysis in these 28 patients were compared with those from another 22 patients with essential thrombocythemia (ET), 10 with myelofibrosis with myeloid metaplasia (MMM), 19 with SP, and 11 healthy volunteers. RESULTS. The 63 patients with PV were followed for a median of 33 months (range 3–324) from the time of initial diagnosis. During this period, 3 patients have died including 2 from acute myeloid leukemia (AML). Disease transformation into either AML or MMM has occurred in 2 and 4 patients, respectively. The median time from diagnosis to the time of mutation analysis was 12 months (range 0–306). JAK2 V617F was detected in 58 of the 63 patients with PV (92%; homozygous in 21%). The clinical phenotype of the 5 patients with wild-type allele was otherwise typical for the disease. A statistical comparison between JAK2 V617F heterozygotes (n=45) and homozygotes (n=13) in PV did not reveal significant associations in regards to age, gender, leukocyte or platelet count at diagnosis, disease duration, or the incidences of thrombosis or bleeding. However, JAK2 V617F homozygotes, compared to their heterozygote counterparts, displayed significantly higher hemoglobin level at diagnosis (p=0.001), increased incidence of pruritus (69% vs. 38%; p=0.04), and a higher rate of fibrotic transformation (23% vs. 2%; p=0.009). The overall (homozygous) JAK2 V617F mutational frequencies in the other study patients with ET, MMM, SP, and healthy controls were 55% (0%), 30% (0%), 0%, and 0%, respectively. The corresponding figures for increased PRV-1 expression in these patients were 18%, 20%, 21%, and 9% as compared to 89% in PV. In patients with either ET or MMM, the likelihood of detecting JAK2 V617F was significantly higher in the presence of an increased PRV-1 expression (83% vs. 38%; p=0.05). Similarly, in patients with PV, homozygous as compared to heterozygous JAK2 V617F correlated with higher levels of PRV-1 expression (p=0.07). CONCLUSIONS. The current clinical study demonstrates a mutant allele dose effect on erythrocytosis, PV-characteristic clinical features, and granulocyte PRV-1 expression in PV. Furthermore, compared to the PRV-1 assay, mutation screening for JAK2 V617F displayed greater specificity in distinguishing PV from SP.

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