Page 1345 - Williams Hematology ( PDFDrive )

1320 Part X: Malignant Myeloid Diseases Chapter 86: Primary Myelofibrosis 1321

an unidentified predisposition gene. 28–30 A large Swedish study found a can be distinguished from secondary myelofibrosis in women by clonal-
significant relative risk (five- to sevenfold) for a familial occurrence of ity studies. The discovery of the JAK2 V617F mutation has permitted this
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another myeloproliferative disease neoplasm, although not specifically marker to be used in assessing clonality (as will mutations in CALR and
primary myelofibrosis. The latter finding may relate to the small number MPL as their determination reaches the clinic). Mutated JAK2-containing
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of cases of primary myelofibrosis in that study. The incidence of the cells were identified in all blood lineages of patients with primary myel-
disease is approximately 0.5 cases per 100,000 population per year in ofibrosis and in the common multipotential hematopoietic cell. 52
northern European countries. 31–34 A survey in Olmstead County, Min- The neoplastic hematopoietic stem cells in primary myelofibrosis
nesota reported an incidence of 1.5 case per 100,000 population per containing the JAK2 V617F mutation behave differently from the same cell
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year and a median age of onset of 67 years, similar to other studies (see population in polycythemia vera when studied in nonobese, diabetic,
above in this section). severe combined immunodeficient mice. Although studied in a non-
human environment, the findings are consistent with the presence of
ETIOLOGY AND PATHOGENESIS JAK2 V617F mutations in three phenotypically different myeloproliferative
diseases: polycythemia vera, essential thrombocythemia, and primary
EXOGENOUS FACTORS myelofibrosis. 53
Animal models allowed the derivation of the murine myelopro-
Exposure to high concentrations of benzene 36–38 or very-high-dose ion- liferative leukemia (mpl) virus, carrying the oncogene v-mpl, which
izing radiation preceded the development of primary myelofibrosis in in mice produced a syndrome having features of a mixed idiopathic
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a very small number of cases in the past. Epidemiologic studies have myelofibrotic–polycythemic disorder (Chap. 111). The availability of
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not determined a relative risk of myelofibrosis after high-dose benzene v-mpl led to the isolation of the thrombopoietin receptor and its lig-
exposure. Lower-level benzene exposure was not found to be associated and thrombopoietin. Later models of myelofibrosis and osteosclerosis,
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with the risk of myeloproliferative disease in a comprehensive study. mimicking some of the important features of human primary myelo-
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Thus, the few case reports must be viewed with caution in assessing fibrosis, were induced in mice by retroviral-mediated overexpression
causation. Benzene in exposures greater than 40 to 200 ppm-years is of thrombopoietin. 56,57 The concomitant high levels of fibroblastic fac-
associated with an increased relative risk of acute myelogenous leu- tors (transforming growth factor [TGF]-β and platelet-derived growth
1
kemia (AML), 41,42 but not of chronic myelogenous leukemias (CMLs; factor [PDGF]) resulted in intense fibrosis. In this model, increased
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Chap. 89) These levels of exposures are far above the current levels per- osteoprotegerin was thought to be the principal cause of osteosclero-
mitted by the Occupational Safety and Health Administration.
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sis. The disease was cured by murine hematopoietic stem cell trans-
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plantation. These findings were extended and led to the discovery of
IMMUNE MECHANISMS the human analogue of v-mpl, c-MPL that encodes the human throm-
Reports of myelofibrosis in patients with lupus erythematosus, have bopoietin receptor. Two gain-of-function somatic mutations, MPL W515L
suggested the possibility of immunologic-mediated hyperplasia of mar- and MPL W515K , were found to be associated with primary myelofibrosis
row connective tissue (see “Immune and Inflammatory Manifestations” and essential thrombocythemia. 60,61 These gain-of-function mutations
2
below). These forms of myelofibrosis are different from the monoclonal may also be germline and in such a case are associated with familial
multipotential hematopoietic cell disease, which is the principal type (hereditary) thrombocytosis. 62
considered in this chapter. A syndrome in mice that results from the GATA-1 (low) mutation
also leads to a phenotype that closely simulates human myelofibrosis.
CLONAL MYELOID DISEASE, ANIMAL MODELS, The mice gradually develop anemia, teardrop poikilocytes, myeloid
immaturity, marrow fibrosis, extramedullary hematopoiesis, and over-
AND ACTIVATING MUTATIONS expression of profibrotic cytokines in marrow. GATA-1 is a transcrip-
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The disease arises from the neoplastic transformation of a single tion factor required for normal megakaryocyte development. GATA-1
hematopoietic multipotential cell, a conclusion derived from the pres- deficiency in mice leads to increased megakaryocytic proliferation,
ence of clonal cytogenetic abnormalities in patients with an identifiable followed by myelofibrosis and osteosclerosis, as a result of exaggerated
chromosomal abnormality and in studies in women with primary mye- elaboration of fibroblast-inducing and osteoblast-stimulating factors. 64,65
lofibrosis who also were heterozygous for isotypes A and B of glucose- The discovery in 2005 that an activating somatic G→T point muta-
6-phosphate dehydrogenase (G6PD). 43,44 Although the nonhematopoi- tion (V617F) in JAK2 was associated with the three major myelopro-
etic tissues of these patients expressed both isotypes, each patient had liferative diseases—polycythemia vera, essential thrombocythemia, and
blood cells with only one G6PD isotype. The findings strongly imply the primary myelofibrosis—has rapidly led to a fuller understanding of the
blood cells of each patient arose from only one transformed stem cell. pathogenesis of these diseases. 48,66 A dominant, gain-of-function muta-
Furthermore, chromosome studies of colonies of hematopoietic pro- tion in the gene JAK2 residing on chromosome 9p24, which encodes the
genitor cells in primary myelofibrosis established that the same clonal JAK2 tyrosine kinase, is present in approximately 50 percent of patients
cytogenetic abnormality is present in erythroblasts, neutrophils, macro- with primary myelofibrosis, in approximately 95 percent of patients
phages, basophils, and megakaryocytes. These studies were confirmed with polycythemia vera (Chap. 84), and in approximately 60 percent
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by (1) examining X-linked restriction fragment length polymorphisms of patients with essential thrombocythemia (Chap. 85), but is absent in
in women with primary myelofibrosis with heterozygosity for X chro- healthy individuals. 67,68 In confirmation, the expression of the mutated
mosome-linked genes 46,47 and (2) verifying the presence of a mutation of human JAK2 gene transferred into mice can induce a myeloprolifera-
codon 12 of the N-RAS gene in five blood cell lineages of a patient with tive disease with features characteristic of the human disorders. 69–74
the disease. 48,49 Lymphocyte derivation from the clone has been noted Homozygosity results from allelic duplication as a result of uniparental
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using mutation in codon 12 of the RAS gene as the marker. Using fluo- disomy of chromosome 9p, not loss of the normal allele corresponding
rescence in situ hybridization (FISH) analysis, T and B lymphocytes were to the mutation. 72
found to be derived from clonal expansion of a multipotential hemato- It is not yet precisely known how JAK2 V617F , the most prevalent
poietic cell in three of four patients with primary myelofibrosis with a mutation, links the three diseases and what modifiers explain the dra-
13q– or 20q– clonal cytogenetic abnormality. Primary myelofibrosis matically different phenotype and expected survival of the patients with
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