Clinical and scientific advances in the philadelphia-chromosome negative chronic myeloproliferative disorders

Abstract

The chronic myeloproliferative disorders are clonal hematopoietic stem cell disorders and include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and agnogenic myeloid metaplasia (AMM). These diseases are characterized by clonal expansion of the myeloid compartment, increased marrow angiogenesis, and varying risks for blastic transformation. A clear molecular abnormality exists (t(9;22) leading to the fusion of BCR-Abl) only for CML, which led to effective targeted therapy (STI-571). Since no similar pathogenetic mechanism has been discovered for the t(9;22) negative chronic myeloproliferative disorders, their respective diagnosis is currently based on a variety of rather cumbersome diagnostic criteria. Polycythemia vera is distinguished from reactive erythrocytosis through erythropoietin independent growth of erythroid progenitors in vitro, suppressed levels of endogenous erythropoietin, possible overexpression of PRV-1 (polycythemia rubra vera-1), decreased c-Mpl expression on megakaryocytes, as well as overexpression of bcl-xL, and potentially aberrant activity of the Jak-Stat pathway. ET is defined by thrombocytosis and is distinguished from reactive states by decreased megakaryocyte c-Mpl expression, and a propensity for thrombosis. AMM has been associated with a variety of observations including increased concentrations of pro-fibrotic cytokines, increased angiogenesis, and myeloid expansion. AMM is often indistinguishable clinically and prognostically from the advanced phases of other CMPD (specifically post-polycythemic and post-thrombocythemia myeloid metaplasia), all of which are subentities of a diagnosis of myelofibrosis with myeloid metaplasia (MMM). The management of CMPD patients is quite varied given the broad range of disease severity and survival observed. The role of stem cell transplantation is limited by the age and comorbidities encountered in CMPD patients. Since no broadly applicable therapy effects the mortality of the CMPD, management currently focuses on the prevention/palliation of disease morbidity (i.e. vascular complications, pruritus, organomegaly, constitutional symptoms). Palliative strategies which currently focus on non-specific myelosuppresion, will hopefully be soon replaced by targeted therapies as insight into pathogenetic mechanisms of these diseases evolves.

Working hypothesis to redefine endothelial progenitor cells

“…CML is characterized by a unique chromosomal translocation, t (9;22), that results in a BCR/ABL fusion gene product. 113 This translocation is present in a multi-potent HSC clone and all the derived progeny. 113 This feature permitted Gunsilius et al 112 to examine EPCs for this genetic mutation.…”

“…113 This translocation is present in a multi-potent HSC clone and all the derived progeny. 113 This feature permitted Gunsilius et al 112 to examine EPCs for this genetic mutation. They reported that in five of six patients, cultured CFU-ECs displayed the translocation, suggesting to Gunsilius et al 112 that EPCs arise from a hemangioblastic precursor.…”

Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells

“…[1][2][3][4][5] A gain-of-function mutation JAK2V617F has been identified in the MPNs, which is present in the granulocytes of approximately 95% of patients with polycythemia vera and 50% of patients with either PMF or essential thrombocythemia. In approximately 10% of patients with JAK2V617F-negative PMF, an additional somatic mutation of the thrombopoietin receptor gene MPL has also been identified.…”

Involvement of mast cells by the malignant process in patients with Philadelphia chromosome negative myeloproliferative neoplasms

“…1,2 Chromosomal abnormalities occur in 25-29% of patients with PV, approximately 50% of patients with PMF; whereas in ET, cytogenetic abnormalities are found infrequently (B8%). 1,3,4 The spectrum of cytogenetic aberrations in Ph À MPNs ranges from numerical gains and losses to structural changes including unbalanced translocations.…”