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.

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.

Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 556-556
Author(s):  
Gerlinde Wernig ◽  
Michael G. Kharas ◽  
Rachel Okabe ◽  
Sandra A. Moore ◽  
Dena S. Leeman ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Murine Model ◽  
Primary Myelofibrosis ◽  
Extramedullary Hematopoiesis ◽  
Cell Number ◽  
Surrogate Endpoints ◽  
Myeloproliferative Disease ◽  
Jak2 Inhibitor

Abstract The JAK2V617F mutation is present in the majority of cases of myeloproliferative disease, including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), and is an attractive candidate for molecularly targeted therapy. However, the potential toxicities of JAK2 inhibition in vivo, and identification of appropriate surrogate endpoints for response, are challenges that may limit clinical usefulness in treatment of these relatively indolent diseases. We report efficacy and assessment of surrogate endpoints for response of a small molecule JAK2 inhibitor, TG101348 in a murine model of polycythemia vera. TG101348 is selective for JAK2 with an in vitro IC50 of ∼3 nM that is ∼334 fold more potent than for inhibition of JAK3. TG101348 showed therapeutic efficacy in the murine model of PV that included a statistically significant reduction in hematocrit, normalization of white blood cell count, a dose dependent reduction/elimination of extramedullary hematopoiesis in the spleen and liver, and marked attenuation of myelofibrosis. Consistent with its selective inhibition of JAK2 and not JAK3, there was no significant change in T-cell number in treated animals. These clinical responses correlated with surrogate endpoints for response, including reduction or elimination of JAK2V617F expressing clones based on quantitative genomic PCR, suppression of JAK2V617F positive endogenous erythroid colony growth of JAK2V617F MPD bone marrow, and inhibition of JAK-STAT signal transduction as assessed by phosphoflow cytometry for phosphorylated STAT5. Thus, TG101348 is efficacious in treatment of a murine model of PV, and surrogate endpoints have been identified that may be of value in clinical trials in humans.

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]

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.

scholarly journals Expression of Jak2V617F causes a polycythemia vera–like disease with associated myelofibrosis in a murine bone marrow transplant model

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4274-4281 ◽  
Author(s):  
Gerlinde Wernig ◽  
Thomas Mercher ◽  
Rachel Okabe ◽  
Ross L. Levine ◽  
Benjamin H. Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Extramedullary Hematopoiesis ◽  
Marrow Transplant ◽  
Myeloproliferative Disease ◽  
Murine Bone Marrow ◽  
Retroviral Integration ◽  
Vitro Analysis

AbstractAn acquired somatic mutation, Jak2V617F, was recently discovered in most patients with polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), and essential thrombocythemia (ET). To investigate the role of this mutation in vivo, we transplanted bone marrow (BM) transduced with a retrovirus expressing either Jak2 wild-type (wt) or Jak2V617F into lethally irradiated syngeneic recipient mice. Expression of Jak2V617F, but not Jak2wt, resulted in clinicopathologic features that closely resembled PV in humans. These included striking elevation in hemoglobin level/hematocrit, leukocytosis, megakaryocyte hyperplasia, extramedullary hematopoiesis resulting in splenomegaly, and reticulin fibrosis in the bone marrow. Histopathologic and flow cytometric analyses showed an increase in maturing myeloid lineage progenitors, although megakaryocytes showed decreased polyploidization and staining for acetylcholinesterase. In vitro analysis of primary cells showed constitutive activation of Stat5 and cytokine-independent growth of erythroid colony-forming unit (CFU-E) and erythropoietin hypersensitivity, and Southern blot analysis for retroviral integration indicated that the disease was oligoclonal. Furthermore, we observed strain-specific differences in phenotype, with Balb/c mice demonstrating markedly elevated leukocyte counts, splenomegaly, and reticulin fibrosis compared with C57Bl/6 mice. We conclude that Jak2V617F expression in bone marrow progenitors results in a PV-like syndrome with myelofibrosis and that there are strain-specific modifiers that may in part explain phenotypic pleiotropy of Jak2V617F-associated myeloproliferative disease in humans.

Polycythemia Vera: New Clinicopathologic Perspectives

2006 ◽  
Vol 130 (8) ◽  
pp. 1126-1132
Author(s):  
Ming Cao ◽  
Randall J. Olsen ◽  
Youli Zu
Keyword(s):  
Polycythemia Vera ◽  
Relevant Literature ◽  
Cell Mass ◽  
Clinical Manifestations ◽  
Janus Kinase ◽  
Myeloproliferative Disease ◽  
Thrombosis Risk ◽  
Hematopoietic Precursor ◽  
Chronic Myeloproliferative Disease ◽  
Primary Bone

Abstract Context.—Polycythemia vera (PV) is a clonal myeloproliferative disease characterized by an erythroid dominant trilineage proliferation of hematopoietic precursor cells. Classified as a chronic myeloproliferative disease, PV represents a histopathologic spectrum of 2 recognized stages, the polycythemic and postpolycythemic phase. The clinical manifestations of hemorrhage, thrombosis, and increased red cell mass are directly related to primary bone marrow dysfunction. Prognosis is strongly associated with thrombosis risk and disease progression; thus, treatment is directed toward minimizing coagulopathic complications and preventing leukemic transformation. Recently, a specific point mutation in the Janus kinase 2 (JAK2) gene was described in a majority of PV patients. The potential diagnostic and/or prognostic value of JAK2V617F is discussed. Objective.—To review important developments from the recent and historical literature. Modern diagnostic criteria and emerging molecular findings are emphasized. Data Sources.—A comprehensive review was performed of the relevant literature indexed in PubMed (National Library of Medicine) and referenced medical texts. Conclusions.—Modified clinical, histologic, and laboratory criteria have clarified the diagnosis of PV. Also, continuing studies on the recently discovered JAK2V617F gene mutation may significantly improve our understanding of PV pathogenesis and facilitate its medical management.

scholarly journals Extramedullary Hematopoiesis Simulating Parasagittal Meningioma

1982 ◽  
Vol 9 (1) ◽  
pp. 49-51 ◽  
Author(s):  
R.A. Kandel ◽  
K.P.H. Pritzker ◽  
A.S. Gordon ◽  
J.M. Bilbao
Keyword(s):  
Intracranial Pressure ◽  
Polycythemia Vera ◽  
Extramedullary Hematopoiesis ◽  
Raised Intracranial Pressure ◽  
Myeloproliferative Disease ◽  
Falx Cerebri ◽  
Myeloid Metaplasia ◽  
Intracranial Tumours ◽  
Parasagittal Meningioma ◽  
Radiologic Features

ABSTRACT:We report a patient with polycythemia vera and myeloid metaplasia of nine years duration who developed raised intracranial pressure related to a mass obliterating the sagittal fissure. Although clinically and radiologically simulating a meningioma, biopsy revealed extramedullary hematopoiesis involving the falx cerebri. Although uncommon, this case illustrates that myeloproliferative disease can present with symptomatology and radiologic features similar to primary intracranial tumours.

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

Abstract 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.

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