Primary myelofibrosis and its paraneoplastic stromal effects.

recommended the use of the name primary myelofibrosis (PMF) for the clinicopathologic entity otherwise known as chronic idiopathic myelofibrosis, agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia. The deliberations of the expert panel took into account the fact that the key pathogenetic process in PMF is no longer idiopathic or agnogenic; PMF is now known to constitute a clonal stem cell disease with recurrent molecular markers (e.g. JAK2V617F, MPLW515L/K) and/or cytogenetic markers (e.g. del(13q), del (20q), +8, +9, and abnormalities involving chromosome 1, 7, and 12). 2 The PMF designation also underscores the characteristic , albeit neither invariable nor specific, association of the underlying clonal myeloproliferation with overt myelofibrosis. 3 However, the bone marrow and splenic stromal changes in PMF, including angiogenesis, are reactive in nature and completely reversible with effective treatment of the primary clonal process. 4,5 Such has been the case also with other myeloid neoplasms that are sometimes associated with similar histological changes. 6-9 This, however, does not undermine the possibility of a direct detrimental effect from these parane-oplastic features on both effective hematopoiesis and the tempo of clonal myeloproliferation. For operational purposes, one can consider two interdependent pathogenetic mechanisms in PMF; a primary megakaryocyte-weighted clonal myeloproliferation and a secondary (paraneoplastic) stromal reaction that includes bone marrow fibrosis, osteosclerosis, angio-genesis, and extramedullary hematopoiesis (EMH). As stated above, current evidence strongly supports the stem cell origin of the clonal myeloproliferation in PMF and this decades-long contention has recently been validated by the demonstration of both cytogenetic and molecular markers of clonality in lymphocytes and myeloid progenitors of patients with PMF. 10-15 What remains at large is the primary clonogenic mutation although both JAK2V617F and MPLW515L/K are now considered serious candidates in this regard. 16-20 For the record, JAK2V617F induces a polycythemia vera-like disease in mice whereas MPLW515L causes a PMF phenotype. 18,21-23 Regardless, about half of the patients with PMF do not display either mutation and the precise pathogenetic role of these mutations, when they are present, remains to be clarified. Other molecular alterations in PMF include decreased expression of the tumor suppressor retinoic acid receptor (RAR)-β2 gene as a result of abnormal promoter methylation, 24 and reduced megakaryocyte/platelet surface expression of MPL. 25 Additional insight into the molecular pathogene-sis of PMF is currently being pursued through global gene expression analysis. The second component of the pathogenetic process in PMF constitutes the bone marrow stromal changes (i.e. collagen …