Download Leukaemia Section Myelofibrosis with myeloid metaplasia (MMM), Idiopathic myelofibrosis, Agnogenic myeloid metaplasia

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Myelofibrosis with myeloid metaplasia (MMM),
Idiopathic myelofibrosis, Agnogenic myeloid
metaplasia
Antonio Cuneo, Francesco Cavazzini
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy
Published in Atlas Database: August 2006
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/Myelofib.html
DOI: 10.4267/2042/38381
This article is an update of: Huret JL. Myelofibrosis with myeloid metaplasia (MMM). Agnogenic myeloid metaplasia. Atlas Genet
Cytogenet Oncol Haematol.1998;2(1):17.
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Clinics and pathology
Disease
Chronic myeloproliferative disorder
Phenotype / cell stem 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.
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.
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.
Treatment
Clinics
The treatment depends on the patient’s 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.
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.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
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Myelofibrosis with myeloid metaplasia (MMM), Idiopathic myelofibrosis, Agnogenic myeloid metaplasia
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.
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.
Cytogenetics
Cytogenetics morphological
References
a) Chromosome lesions:
The absence of the t(9;22)/BCR-ABL fusion is an
absolute diagnostic requirement. Approximately 4050% of the patients analyzed at diagnosis show a clonal
defect. The proportion of cytogenetically abnormal
cases increases at disease transformation into acute
leukemia, were up to 90% of the cases carry a clonal
defect. Non-random chromosome aberrations are
del(13q), del(20q) and gain of 1q. These abnormalities
represented 65% of abnormal cases in a study. Other
recurrent chromosome aberrations include trisomy 8
and del(12p), monosomy 7/del(7q), der(6)t(1;6)(q2123;p21.3). The latter abnormality leads to trisomy
1q21-23 to 1qter and to loss of 6p21 to 6pter.
FISH on deparaffinized bone biopsies showed a 56%
incidence of cytogenetic lesions in a study using probes
for 7q31, 12p, 13q14, 17p13, 20q13, 21q22, cen7,
cen8, cen11 and cen17.
b) Prognostic significance:
The presence of abnormal karyotype does not appear to
be an independent prognostic factor, whereas +8, 12p
deletion and -7/7q- were associated with an inferior
outcome at multivariate analysis.
Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM, Jones N,
Watmore A, Potter A. Cytogenetic abnormalities and their
prognostic significance in idiopathic myelofibrosis: a study of
106 cases. Br J Haematol 1997;98:96-102.
Tefferi A, Mesa RA, Schroeder G, Hanson CA, Li CY, Dewald
GW. Cytogenetic findings and their clinical relevance in
myelofibrosis with myeloid metaplasia. Br J Haematol
2001;113:763-771.
Bacher U, Haferlach T, Kern W, Hiddemann W, Schnittger S,
Schoch C. Conventional cytogenetics of myeloproliferative
diseases other than CML contribute valid information. Ann
Hematol 2005;84:250-257.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N,
Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott
MA, Erber WN, Green AR. Cancer Genome Project. Acquired
mutation of the tyrosine kinase JAK2 in human
myeloproliferative disorders. Lancet 2005;365:1054-1061.
Dingli D, Grand FH, Mahaffey V, Spurbeck J, Ross FM,
Watmore AE, Reilly JT, Cross NC, Dewald GW, Tefferi A.
Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality
in myelofibrosis with myeloid metaplasia. Br J Haematol
2005;130:229-232.
Hoffman R, Ravandi-Kashani F, IN: Hoffman R, Benz EJ,
Shattil SJ, Furie B, Cohen HJ, Silbertsein LE, McGlave P
(Eds). Idiopathic myelofibrosis. Hematology. Basic Principles
and practice. Elsevier, Philadelphia, Pennsylvania, 2005
pp1255-1275.
Genes involved and Proteins
Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA,
Tefferi A. Leukemic transformation in myelofibrosis with
myeloid metaplasia: a single-institution experience with 91
cases. Blood 2005;105:973-977.
JAK2
Location: 9p24
Note: Janus Kinase JAK2 mutation (See also
Polycythemia Vera).
Protein
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
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
Cuneo A, Cavazzini F
Strasser-Weippl K, Steurer M, Kees M, Augustin F, Tzankov A,
Dirnhofer S, Fiegl M, Gisslinger H, Zojer N, Ludwig H.
Chromosome 7 deletions are associated with unfavorable
prognosis in myelofibrosis with myeloid metaplasia. Blood
2005;105:4146.
Vainchenker W. Constantinescu SN. A Unique Activating
Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera
and Allows a New Classification of Myeloproliferative
Diseases. ASH Educational Book 2005:195-200.
Campbell PJ, Griesshammer M, Döhner K, Döhner H, Kusec
R, Hasselbalch HC, Larsen TS, Pallisgaard N, Giraudier S, Le
Bousse-Kerdilès MC, Desterke C, Guerton B, Dupriez B,
Bordessoule D, Fenaux P, Kiladjian JJ, Viallard JF, Brière J,
Harrison CN, Green AR, Reilly JT. V617F mutation in JAK2 is
associated with poorer survival in idiopathic myelofibrosis.
Blood 2006;107:2098-2100.
Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA,
Wadleigh M, Steensma DP, Elliott MA, Wolanskyj AP, Hogan
WJ, McClure RF, Litzow MR, Gilliland DG, Tefferi A. MPL515
mutations in myeloproliferative and other myeloid disorders: a
study of 1182 patients. Blood 2006;108(10):3472-3476.
Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M,
Cuker A, Wernig G, Moore S, Galinsky I, Deangelo DJ, Clark
JJ, Lee SJ, Golub TR, Wadleigh M, Gilliland DG, Levine RL.
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Myelofibrosis with myeloid metaplasia (MMM), Idiopathic myelofibrosis, Agnogenic myeloid metaplasia
MPLW515L Is a Novel Somatic Activating Mutation in
Myelofibrosis with Myeloid Metaplasia. PLoS Med
2006;3:e270.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
Cuneo A, Cavazzini F
This article should be referenced as such:
Cuneo A, Cavazzini F. Myelofibrosis with myeloid metaplasia
(MMM), Idiopathic myelofibrosis, Agnogenic myeloid
metaplasia. Atlas Genet Cytogenet Oncol Haematol.2007;
11(1):27-29.
29