title: Stem cell defects in Philadelphia chromosome negative chronic myeloproliferative disorders: a phenotypic and molecular puzzle?
abstract: Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph(-) CMPD) comprise a group of heterogenous haematological stem cell disorders. These diseases harbour a pathological bone marrow stem cell which overwhelms normal stem cells due to sustained and uncontrolled proliferation. By clonal evolution, acute leukaemia or bone marrow fibrosis evolve in a proportion of cases with as yet unknown underlying mechanisms. Previously, groundbreaking investigations in Ph(-) CMPD detected an acquired mutation in the Janus kinase 2 (JAK2) in the majority of patients with polycythaemia vera (PV) and in up to 50% of patients with essential thrombocythaemia (ET) and chronic idiopathic myelofibrosis (CIMF). Unlike the stem cell defect in Philadelphia chromosome-positive chronic myeloid leukaemia only a subfraction of clonally proliferating haematopoiesis may be affected by the JAK2 mutation. More recently, another mutation in the juxtamembrane domain of the thrombopoietin receptor Mpl was discovered in about 5% of patients with CIMF and ET. In accordance with the uncontrolled Abl kinase activity in Ph(+) chronic myloid leukaemia these mutations in Ph(-) CMPD apparently represent a key to unlock some of the as yet unknown basic molecular defects and this raises hope for an upcoming efficient targeted therapy. However, neither the JAK2(V617F) nor the Mpl(W515L/K) provide the initiating molecular events. Moreover, apart from distinction between reactive and neoplastic lesions, detection of these mutations does not allow a clear-cut discrimination between the particular subtypes. This review will focus on previous and recent findings in the field of molecular defects in Ph(-) CMPD.
authors.affiliation: Institute of Pathology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Bock.Oliver@MH-Hannover.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Bock
authors.forename: Kais
authors.initials: K
authors.lastname: Hussein
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
mesh_terms: D002869:Chromosome Aberrations; D016207:Cytokines / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010677:Philadelphia Chromosome; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D013926:Thrombopoietin / Q000378:metabolism
chemical_list: D016207:Cytokines; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin; D053614:Janus Kinase 2