Myelofibrosis with Myeloid Metaplasia (MMM)
Idiopathic myelofibrosis
Agnogenic myeloid metaplasia
2006-08-01 Antonio Cuneo , Antonio Cuneo
Affiliation
1.Hematology Section, Dept. Of Biomedical Sciences, University of Ferrara, 44100 Ferrara Italy
2.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Clinics and Pathology
Disease
Chronic myeloproliferative disorder
Phenotype stem cell origin
The disease is a chronic myeloproliferative disorder originating from a mutated pluripotent stem cell capable of producing red blood cells, granulocytes, megakaryocytes and lymphoid cells. Fibrosis of the marrow is the hallmark of the disease, however fibroblasts are not part of the malignant process and fibrosis represents a reaction of marrow stromal cells.
Epidemiology
MMM has an incidence of 0.3 to 1.5 new cases per year in 100.000 persons. Male predominance was observed in some studies and not confirmed in others. The average age at diagnosis is 60 years. Exposure to radiation and to organic solvents increases the risk of developing MMM.
Clinics
MMM usually presents with fatigue, weight loss, splenomegaly with or without symptoms. Anemia and various alterations of the white blood cell and/or platelet count are frequently seen at diagnosis. Thrombocytopenia-related bleeding may occur. MMM must be distinguished from myelodysplasia with fibrosis, from acute megakayoblastic leukemia and acute myelofibrosis.
As the disease progresses, increased marrow fibrosis with severe symptomatic peripheral cytopenias and extramedullary hemopoiesis predominate, with consequent massive splenomegaly, hepatomegaly with portal hypertension, pulmonary hypertension. Leukemic transformation may represent the terminal event in 5-20% of the cases.
As the disease progresses, increased marrow fibrosis with severe symptomatic peripheral cytopenias and extramedullary hemopoiesis predominate, with consequent massive splenomegaly, hepatomegaly with portal hypertension, pulmonary hypertension. Leukemic transformation may represent the terminal event in 5-20% of the cases.
Cytology
Teardrop poikilocytosis and leukoerythroblastosis are present in the peripheral blood (PB) smear. Platelet are increased in size. The bone marrow is usually hypercellular at presentation with remarkably increased megakaryocytes and, to a lesser degree, granulocytes. Reticulin fibrosis is always present. Hemopoietic cellularity is patchy, with some areas showing hypercellularity and other being depleted of hemopoietic cells. The spleen histology shows extramedullary hemopoiesis involving predominantly the sinusoids.
Treatment
The treatment depends on the patient¹s general condition and symptoms. Supportive treatment is required for anemia and profound thrombocytopenia. Cytoreductive treatment with busulphan, hydroxyurea, thioguanine, low-dose melphalan or chlorambucil, interferon-a may be useful to control progressive splenomegaly. Irradiation of the spleen may be also employed. Danazol or low-dose dexamethasone can be used to ameliorate anemia. Allogeneic bone marrow transplantation should be considered for patients aged 60 years or less.
Prognosis
The median survival is approximately 5 years. Causes of death include infection, leukemic transformation, bleeding, hepatic failure with portal hypertension due to myeloid metaplasia, heart failure.
Genes Involved and Proteins
Gene name
JAK2 (janus kinase 2)
Location
9p24.1
Note
Janus Kinase JAK2 mutation (See also Polycythemia Vera).
Protein description
A valine to phenylalanine substitution at position 617 (JAK2 V617F mutation) is present in approximately 50-55% of the patients leading to constitutive kinase activity.
The mutated JAK2 protein binds to the cytoplasmic domain of Epo-R and promotes signalling independent of Epo stimulation. The JAK2 protein is coded for by a gene mapping at 9p and it is activated upon erythropoietin binding to the receptor. JAK2 signalling involves the phosphorylation of several Y residues at the Epo receptor with activation of STAT, MAP kinase PI-3-kinase and AKT. These events lead to survival and proliferation of erythroid progenitors. JAK2 is involved in intracellular signalling following stimulation by IL3, TPO and GM-CSF, and erythroid progenitors in PV are hypersensitive to stimulation by these cytokines.
Patients with JAK2 V617F mutation showed high white blood cell counts, required less transfusions and had an inferior outcome in a study.
In 5-9% of the patients a gain-of-function mutation of the thrombopoietin receptor (MPL) gene can be found, determining activation of the JAK-STAT pathway.
The mutated JAK2 protein binds to the cytoplasmic domain of Epo-R and promotes signalling independent of Epo stimulation. The JAK2 protein is coded for by a gene mapping at 9p and it is activated upon erythropoietin binding to the receptor. JAK2 signalling involves the phosphorylation of several Y residues at the Epo receptor with activation of STAT, MAP kinase PI-3-kinase and AKT. These events lead to survival and proliferation of erythroid progenitors. JAK2 is involved in intracellular signalling following stimulation by IL3, TPO and GM-CSF, and erythroid progenitors in PV are hypersensitive to stimulation by these cytokines.
Patients with JAK2 V617F mutation showed high white blood cell counts, required less transfusions and had an inferior outcome in a study.
In 5-9% of the patients a gain-of-function mutation of the thrombopoietin receptor (MPL) gene can be found, determining activation of the JAK-STAT pathway.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 15692838 | 2005 | Conventional cytogenetics of myeloproliferative diseases other than CML contribute valid information. | Bacher U et al |
| 15781101 | 2005 | Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. | Baxter EJ et al |
| 16293597 | 2006 | V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. | Campbell PJ et al |
| 16029451 | 2005 | Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia. | Dingli D et al |
| 15388582 | 2005 | Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. | Mesa RA et al |
| 16834459 | 2006 | MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. | Pikman Y et al |
| 9233570 | 1997 | Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases. | Reilly JT et al |
| 11380468 | 2001 | Cytogenetic findings and their clinical relevance in myelofibrosis with myeloid metaplasia. | Tefferi A et al |
| 16304380 | 2005 | A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases. | Vainchenker W et al |
Citation
Antonio Cuneo ; Antonio Cuneo
Myelofibrosis with Myeloid Metaplasia (MMM)
Idiopathic myelofibrosis
Agnogenic myeloid metaplasia
Atlas Genet Cytogenet Oncol Haematol. 2006-08-01
Historical Card
1998-01-01 Myelofibrosis with Myeloid Metaplasia (MMM)Idiopathic myelofibrosisAgnogenic myeloid metaplasia by Jean-Loup Huret Affiliation
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
1997-08-01 Myelofibrosis with Myeloid Metaplasia (MMM)Idiopathic myelofibrosisAgnogenic myeloid metaplasia by Jean-Loup Huret Affiliation
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
