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PubMedDate not supplied

Palliative splenectomy in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder in which the accumulation and growth of circulating myeloid progenitors in the spleen lead to pathologic enlargement of the organ with resulting mechanical discomfort, hypercatabolic symptoms, anemia, thrombocytopenia, and portal hypertension. Medical therapy and splenic irradiation may be of benefit in certain patients, yet many may still require splenectomy to palliate their symptoms. Although there is no clear survival advantage to splenectomy in MMM, the procedure can result in substantial palliation of symptoms. However, the surgical procedure is associated with an approximately 9% mortality rate, and the postsplenectomy occurrence of extreme thrombocytosis, hepatomegaly, and leukemic transformation is of major concern. The management of splenomegaly and the role of splenectomy in MMM are discussed in this review.

Disease Management↗
PubMed2005

Juvenile rheumatoid arthritis with myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia is defined as a myeloproliferative disorder characterized by leukoerythroblastosis, tear drop erythrocytes, extramedullary hematopoesis and varying degree of myelofibrosis. It may be idiopathic or secondary to a large number of conditions. Here is a rare case of myelofibrosis occurring in a patient with juvenile rheumatoid arthritis.

Anti-Inflammatory Agents↗
PubMed2004

RARbeta2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem-cell disorder that leads to ineffective hematopoiesis, bone marrow fibrosis, and extramedullary hematopoiesis. The molecular mechanisms underlying the development of this myeloproliferative syndrome are currently unknown. In order to identify tumor suppressor genes that may be involved in the disease process, we performed an analysis for loss of heterozygosity (LOH) in CD34+ cells from 29 patients with MMM. We observed a frequency of allelic loss on chromosomal arm 3p in 24% of cases. Detailed mapping of 3p revealed a distinct region of deletion at 3p24. Among the genes known to map within this region is the retinoic acid receptor-beta (RARbeta2) gene. To determine whether RARbeta2 gene activity is diminished in this disease, we analysed its expression in CD34+ cells from 17 patients with MMM using quantitative PCR. Our results indicate that expression of RARbeta2 is significantly decreased in 100% of patient samples compared to that in CD34+ cells from 10 normal individuals. Since allelic loss at 3p24 occurs in <25% of patients, we investigated the contribution of epigenetic modifications to RARbeta2 inactivity. Using methylation-specific PCR, we found hypermethylation of RARbeta2 in 16 of 18 patients (89%), while the methylated form of the gene was absent in CD34+ cells from nine normal individuals. Our results suggest that RARbeta2 acts as a tumor suppressor gene in MMM and that epigenetic changes are the most significant determinants of RARbeta2 gene activity in these patients.

Base Sequence↗
PubMed2000

Lack of interferon-alpha-induced tyrosine phosphorylation of Vav proto-oncogene in patients with myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is an uncommon chronic myeloproliferative disorder characterized by clonal stem cell proliferation and reactive non-clonal proliferation of bone marrow fibroblasts with fibrosis. In the absence of curative therapy, the current management for the majority of patients is directed towards alleviation of symptoms and improvement in quality of life. A number of experimental therapies have been investigated, among which is the use of type I interferon (IFN)-alpha, whose overall results are disappointing. We recently showed that the Vav proto-oncogene product, p95Vav, which is phosphorylated under IFN-alpha treatment, associates with both chains that constitute the functional type I IFN receptor and contributes to the antiproliferative effects of IFN-alpha. The involvement of p95Vav in IFN-alpha signalling and the frequent non-responsiveness of patients to IFN-alpha led us to investigate for any functional defect(s) of Vav in response to IFN in MMM patients. Our results showed that in the majority of patients Vav is constitutively hyperphosphorylated and that IFN-alpha failed to increase substantially such a tyrosine phosphorylation of p95Vav.

Adult↗
PubMed2004

Angiogenesis and anti-angiogenic therapy in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem cell disorder that is characterized by florid bone marrow stromal reaction including collagen fibrosis, osteosclerosis, and angiogenesis. Almost all patients with MMM display increased bone marrow microvessel density (MVD) and the extent is among the highest in hematological malignancies. This particular information has encouraged the therapeutic use of anti-angiogenic drugs in MMM. In the current review, we summarize the general concepts regarding angiogenesis, assessment of angiogenesis in hematological malignancies and then the current literature on angiogenesis and anti-angiogenic therapy in MMM.

Angiogenesis Inhibitors↗
PubMed2005

TPO/Mpl Studies in Agnogenic Myeloid Metaplasia.

BACKGROUND: Agnogenic myeloid metaplasia (AMM) is one of the Philadelphia chromosome negative myeloproliferative disorder and is diagnosed by hyperplasia of atypical megakaryocytes, hepatosplenomegaly, extramedullary hematopoiesis and bone marrow fibrosis. Fibrosis is considered to be a secondary consequence of enhanced levels of fibrogenic growth factors such as TGF beta1, bFGF and PDGF produced by enhanced numbers of megakaryocytes, while the primary cause is considered to be the enhanced proliferation of a defective stem cell. We have previously reported that thrombopoietin (TPO) is elevated in patients with AMM. Others have reported that Mpl protein is decreased in these patients. Since TPO is essential for the development of megakaryocytes, and Mpl protein is the receptor for TPO, we extended the study of TPO/Mpl to in vitro and in vivo cell culture systems to better understand the mechanism that leads to reduced Mpl protein in AMM patients. RESULTS: Plasma TPO levels were significantly elevated and Mpl protein levels were significantly reduced in AMM patients in concordance with previous studies. Platelet Mpl transcripts in AMM were however similar to those in controls. We also cloned Mpl cDNA from AMM patients and tested for their ability to make functional proteins in vitro and in the in vivo system of 293 T human embryonic kidney cells. Their expression including the glycosylated forms was similar to those from the controls. We also measured the level of translation initiation factor, eIF4E and found it to be increased in patients with AMM demonstrating that the reduced Mpl protein may not be due to translation defects. CONCLUSIONS: Our studies using the in vitro and in vivo systems further confirm that reduced Mpl protein levels are not due to defects in its transcription/translation. Reduced Mpl protein could be due to its increased internalisation owing to enhanced plasma TPO or in vivo intrinsic defects in patients with AMM.

Journal Article↗
PubMed2006

Experimental therapy in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterised by constitutional symptoms, progressive anaemia and extramedullary haematopoiesis. There are no curative therapies available for patients with MMM apart from stem cell transplantation, which is associated with significant morbidity and mortality, and for which most patients are not suitable candidates. Traditional pharmacological therapy of MMM has focused on the palliation of symptoms associated with myeloproliferation and correction of cytopoenias. Recently, new findings regarding the molecular basis of MMM and the pathogenesis of the associated bone marrow stromal reaction have provided both basic and clinical researchers with invaluable tools to develop effective targeted therapies for patients with MMM. Several novel treatment strategies are being investigated including antiangiogenic agents, signal transduction inhibitors, inhibitors of fibrogenesis and small-molecule inhibitors of the JAK2(V617F )mutation. This article reviews the current status of experimental novel therapies for MMM.

Angiogenesis Inhibitors↗
PubMed2003

The forgotten myeloproliferative disorder: myeloid metaplasia.

Myelofibrosis with myeloid metaplasia is a hematologic disorder currently classified with polycythemia vera and essential thrombocythemia as a chronic myeloproliferative disease. The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years. Clinical manifestations include massive splenomegaly, progressive anemia, profound constitutional symptoms, and extramedullary hematopoiesis. The diagnosis is confirmed by bone marrow examination after other causes of myelofibrosis are ruled out. Median survival is 5 years and causes of death include leukemic transformation. Prognosis is adversely affected by the presence of anemia (hemoglobin <10 g/dl), leukopenia or leukocytosis (white blood cells >30,000/ micro l), circulating blasts, and hypercatabolic symptoms. Conventional treatment is palliative and does not improve survival. In this regard, androgen preparations, corticosteroids, and erythropoietin are useful for the treatment of disease-associated anemia. Symptomatic splenomegaly is best managed by cytoreductive therapy or surgical removal. Radiation therapy is most useful in the treatment of nonhepatosplenic extramedullary hematopoiesis. New treatment approaches include the use of thalidomide alone or in combination with prednisone and hematopoietic stem cell transplantation.

Humans↗
PubMed2003

Critical review of pathogenetic mechanisms in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia is an uncommon chronic myeloproliferative disorder characterized by extramedullary hematopoiesis associated with varying degrees of bone marrow fibrosis (hematopoiesis is clonal and fibrosis is a polyclonal reactive process). The primary defect in a pluripotent stem cell is still unknown. However, advances have been made during the past few years in the knowledge of the pathogenetic mechanisms in this disorder. This review focuses on current data on the cellular and molecular mechanisms possibly participating in the development of the disease.

Growth Substances↗
PubMed1991

Clonal granulocytes and bone marrow cells in the cellular phase of agnogenic myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) belongs to the group of myeloproliferative syndromes. It is characterized by a sustained proliferation of megakaryocytes and increased medullary reticulin fibers. Until now the cellular phase at onset of the disease has not been analyzed for clonality of the hematopoietic cells. In this study we used X-linked restriction length polymorphism (RFLP) analysis to investigate the clonality of granulocytes and bone marrow cells from the cellular phase and advanced stages of the disease. In each of 12 heterozygous females, monoclonality of granulocytes or total bone marrow cells could be demonstrated. These results show that the cellular phase represents a monoclonal, and hence a probably neoplastic, proliferation of a pluripotent stem cell. The monoclonality of granulocytes present at the onset of disease should allow analysis of DNA of these easily accessible peripheral cells for the detection of specific clonal aberrations.

Adult↗
PubMed1987

Effects of recombinant alpha and gamma interferons on the in vitro growth of circulating hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM) from patients with myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder due to clonal expansion of a pluripotent hematopoietic progenitor cell with secondary marrow fibrosis. No definitive treatment has as yet been devised for this condition, which shows a marked variability in clinical course. To evaluate whether excessive hematopoietic progenitor cell proliferation could be controlled by recombinant human interferon alpha (rIFN-alpha) and gamma (rIFN-gamma), we studied the effects of these agents on the in vitro growth of pluripotent and lineage-restricted circulating hematopoietic progenitor cells in 18 patients with MMM. A significant increase in the growth (mean +/- 1 SEM) per milliliter of peripheral blood of CFU-GEMM (594 +/- 253), CFU-Mk (1,033 +/- 410), BFU-E (4,799 +/- 2,020) and CFU-GM (5,438 +/- 2,505) was found in patients as compared with normal controls. Both rIFN-alpha and rIFN-gamma (10 to 10(4) U/mL) produced a significant dose-dependent suppression of CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM growth. Concentrations of rIFN-alpha and rIFN-gamma causing 50% inhibition of colony formation were 37 and 163 U/mL for CFU-GEMM, 16 and 69 U/mL for CFU-Mk, 53 and 146 U/mL for BFU-E, and 36 and 187 U/mL for CFU-GM, respectively. A marked synergistic effect was found between rIFN-alpha and rIFN-gamma: combination of the two agents produced inhibitory effects greater than or equivalent to those of 10- to 100-fold higher concentrations of single agents. These studies (a) confirm that circulating hematopoietic progenitors are markedly increased in MMM, (b) indicate that these presumably abnormal progenitors are normally responsive to rIFNs in vitro, and (c) show that IFNs act in a synergistic manner when used in combination. Because rIFN-gamma can downregulate collagen synthesis in vivo, this lymphokine could be particularly useful in the treatment of patients with MMM.

Antibodies, Monoclonal↗
PubMed1996

Differential expression of transforming growth factor-beta, basic fibroblast growth factor, and their receptors in CD34+ hematopoietic progenitor cells from patients with myelofibrosis and myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a myeloproliferative disorder characterized by clonal expansion of hematopoiesis and marrow fibrosis. Previous results from our group have shown an increased production of two potent fibrogenic factors also involved in the regulation of primitive hematopoietic cells, namely transforming growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF), in patients with MMM. It is likely to assume that the myeloproliferation characteristic of this disease may result from an abnormal proliferation of CD34+ hematopoietic progenitors. Thus, we were particularly concerned in studying the gene and protein expression of these cytokines and their receptors in CD34+ progenitors purified from the peripheral blood of MMM patients by using semiquantitative reverse transcriptase-polymerase chain reaction and immunolabeling methods. Our data showed that the expression of TGF-beta1 is not altered in patients CD34+ cells; in contrast, the expression of TGF-beta type II receptor is significantly decreased in such cells, as compared with CD34+ cells from healthy subjects. Regarding bFGF, the very low expression of the cytokine and its type I and II receptors detected in normal CD34+ cells contrasts with that observed in patients' CD34+ cells, which is significantly higher. Our results might be a clue for a better understanding of the mechanism(s) involved in the dysregulation of hematopoiesis in MMM. Actually, the increased expression of bFGF and its receptors associated with the reduction of the TGF-beta binding receptor in CD34+ progenitors from MMM patients might facilitate the expansion of hematopoietic progenitors, not only by stimulating their growth and/or survival, but also by overcoming negative regulatory signals.

ADP-ribosyl Cyclase↗
PubMed1992

Agnogenic myeloid metaplasia in children.

Agnogenic myeloid metaplasia is a chronic myeloproliferative disorder characterized by splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, teardrop-shaped red blood cells, and fibrosis of the bone marrow. It is a disease of adults, with only one case report in the pediatric literature. The symptoms of the patient in this case clearly fit the diagnostic criteria of this disease. Myelofibrosis in children is usually of the acute type, presenting in infancy and running a fulminant, fatal course with minimal or mild splenomegaly. Red blood cells are usually normal on morphologic examination. Three infants, including two siblings, presented at ages 9, 10, and 16 months with clinical and laboratory findings consistent with agnogenic myeloid metaplasia. The occurrence of the disease in these siblings is suggestive of an autosomal recessive mode of inheritance.

Biopsy↗
PubMed1982

Ascites in agnogenic myeloid metaplasia: association with peritoneal implant of myeloid tissue and therapy.

The case of a patient with agnogenic myeloid metaplasia and myelofibrosis engrafted upon a longstanding treated case of polycythemia rubra vera and presenting with ascites due to peritoneal implants of myeloid tissue is presented. Comments on the differential diagnosis of ascites in general, and especially in myelofibrosis, are entered. The specific simple methodology for the confirmation of this diagnosis through microscopic examination of the sediment of the ascitic fluid for the detection of megakaryocytes and erythroblasts is presented. Radiotherapy in moderate amounts offers a very effective and long-lasting form of this entity.

Aged↗
PubMed1975

Myelofibrosis-myeloid metaplasia in childhood.

A child with idiopathic myeloid metaplasia is described and her course contrasted with another child having myeloid metaplasia secondary to reticulum cell sarcoma. Despite prior reports the idiopathic form of illness may pursue a relatively indolent course in children. A thorough search should be made for underlying disease when myeloid metaplasia is first diagnosed.

Child↗
PubMed1986

Ultrastructure of sinusoids in patients with agnogenic myeloid metaplasia.

Four patients with agnogenic myeloid metaplasia underwent liver biopsies. Under light microscopy, sinusoidal infiltration was very mild or moderate, liver architecture was normal with sinusoids slightly dilated and the perisinusoidal collagen network was increased. Under electron microscopy, in perfusion-fixed sinusoids, the following abnormalities were noticed. a) Presence of hemopoietic cells (erythroid, megakaryocytic, lymphoid, myeloid) at different stages of maturation. More frequently observed in the lumen than in the Disse space, they were usually isolated and never exceeded 2 or 3 cells. In the Disse space, hepatocytes in contact with hemopoietic cells were devoid of microvilli. In the lumen they were close to endothelial cells and Kupffer cells. Kupffer cells were numerous with intense phagocytic activity. b) Numerous collagen bundles encircling sinusoids. c) Transformation of perisinusoidal cells into transitional cells with few lipids, prominent RER, long and thick processes containing filaments sometimes condensed below the plasma membrane. Although only one patient showed clinical evidence of portal hypertension of sinusoidal origin, these results suggest that hepatic vascular resistance might be raised in agnogenic myeloid metaplasia.

Cell Adhesion↗
PubMed2005

Agnogenic myeloid metaplasia with pulmonary hematopoiesis.

Agnogenic myeloid metaplasia (AMM) is characterized by bone marrow fibrosis, splenomegaly and leukoerythroblastic anemia and is frequently accompanied by extramedullary hematopoiesis (EMH). Pulmonary interstitial EMH associated with myelofibrosis has rarely been described in the medical literature and is usually fatal. We report the case of a 77-year-old man with agnogenic myeloid metaplasia (AMM) treated with hydroxyurea, who seven years after diagnosis presented with dyspnea and severe hypoxemia. Radionuclide bone marrow scanning demonstrated increased tracer activity on the bases of both lungs, consistent with non-hepatosplenic EMH. Pulmonary EMH is rare in patients with AMM, but should be considered in patients with hypoxemia and respiratory distress.

Aged↗