Review Article Molecular Defects in Chronic Myeloproliferative Disorders

With the exception of chronic myeloid leukemia (CML), the molecular defects in chronic myeloproliferative disorders (MPDs) have not been elucidated. This poor molecular understanding may contribute to the poor and frequently inaccurate classification of these diseases. MPDs are characterized by clonal proliferation of differentiated myeloid cells, and their manifestation can overlap with those of myelodysplastic syndrome (MDS). For example, various degrees of dysplasia can be seen in chronic myelomonocytic leukemia (CMML), along with significant proliferation in hematopoietic elements in the bone marrow and peripheral blood. Similar proliferation can be seen in some MDS patients, but without effective hematopoiesis leading to pancytopenia. In fact, for this reason, many pathologists and hematologists consider CMML a category independent of MPDs and different from MDS (1). The traditional MPDs include CML, polycythemia vera (PV), essential thrombocythemia (ET), and agnogenic myeloid metaplasia (AMM) (2,3). However, entities such as chronic neutrophilic leukemia (CNL) (4,5), hypereosinophilic syndrome (6,7), mastocytosis (8,9), and the 8p11 myeloproliferative syndrome (10,11) are also considered MPDs. Discussing these entities alongside classical MPDs is important, because it may provide information on the common biology and molecular abnormalities between these clinically overlapping diseases. Despite the rarity of 8p11 myeloproliferative syndrome, its molecular defects are better characterized than those in most of the MPDs. This is due to its association with a specific cytogenetic abnormality. As molecular techniques improve and genome-wide screening becomes more available, defining the molecular abnormalities underlying other MPDs will become more feasible. Better understanding of molecular abnormalities in CML has lead to significant advances in treatment and management. The hope is that with better understanding of the molecular defects in the rest of the MPDs, better therapies will be developed. In this review, we discuss the known molecular and biological abnormalities in various MPDs and speculate on a general molecular abnormality or pathway that these diseases may share. We do not discuss the substantial research that has established the clonal nature of primary MPDs, which involve G6PD and X-chromosome activation (12–16). Rather, our discussion will be restricted to acquired primary MPDs. We also do not address hereditary or secondary MPDs.