Proliferation and Differentiation of Erythropoietic and Megakaryopoietic Progenitor Cells: Molecular Mechanisms in Polycythemia vera and Essential Thrombocythemia
An essential feature of the chronic myeloproliferative disorders (MPDs) is an impairment in control of the numbers of hematopoietic progenitor cells without a profound loss in their differentiation capacity. This contrasts with the situation in the acute leukemias, for example, where both the control of progenitor cell numbers and the controls of their differentiation capacity become deregulated. Yet, chronic MPDs not infrequently undergo transformation to acute leukemias. This fact suggests that investigation of the MPDs might help to throw light on fundamental aspects of malignant hematopoietic disease.
The chronic MPDs are a family of neoplastic, often fatal, clonal conditions, each arising as a regulatory defect in a pluripotential stem cell, and characterized clinicopathologically by hyperplasia of all 3 myeloid lineages, but in which only one lineage usually predominates. The basis for this unilineal emphasis is unknown. With the help of a quantitative colony assay method that measures sensitivity to cytokines under strictly serum-free conditions, we in 1994 observed that circulating erythroid progenitor cells in patients with the MPD polycythemia vera (PV) were strikingly hypersensitive to insulin-like growth factor I (IGF-I), though having normal sensitivity to erythropoietin (EPO). IGF-I can promote erythropoiesis in the same manner as EPO, but normally requires a much higher concentration to do this. Median IGF-I sensitivity ratios in PV reached more than 4,000 (range 77-20,000) times normal. This IGF-I hypersensitivity, which could be shown by monoclonal antibody to operate through the IGF-I receptor, was specific to the erythroid lineage, since it did not affect granulocyte-macrophage or megakaryocyte colony formation by circulating progenitors from the same patients. We have shown that ambient concentrations of IGF-I in PV are normal; thus hypersensitivity to IGF-I appears to be one condition responsible for PV being a predominantly erythroid disease. Clonal IGF-I hypersensitivity would also provide an attractive explanation for the clinicopathological emphasis on the erythroid lineage in PV despite the origin of this disorder in a pluripotential stem cell.
Cytokine-induced signaling pathways are negatively regulated by, among other factors, suppressors of cytokine signaling (SOCS) proteins. Socs3, for example, is expressed at low levels in adult tissues, but is highly expressed in fetal liver erythroid progenitor cells. Transgenic embryos that constitutively overexpress Socs3 have no detectable erythropoiesis in their livers. In contrast, a proportion of Socs3-/- embryos die exhibiting a massive erythrocytosis throughout the embryo. Expression of the Socs3 gene appears to be developmentally regulated, and may inhibit cytokine signaling at key periods of embryonic and post-natal life. These considerations raise the interesting question 'What is the status of Socs gene expression in the polycythemias of mouse and man'?
The classical generalization that another MPD, essential thrombocythemia (ET), is a monoclonal disorder arising in a pluripotential stem cell has recently been challenged on the basis of clonality assays indicating that in as many as 30% of patients diagnosed as having ET, the cells were found to be non-clonal. The problem with this conclusion is that ET is essentially a diagnosis of exclusion: No single specific marker for the condition exists. Thus the diagnosis is often uncertain, and any generalization concerning the clonal or non-clonal nature of this clinical diagnostic entity is therefore open to question. We have reported that among patients diagnosed as having ET, a high proportion (~90%) have megakaryocytic progenitor cells that are hypersensitive to thrombopoietin (TPO) in vitro. The hypersensitivity appeared to be specific with respect to disease, to cytokine, and to cell lineage. Accordingly, we are now comparing the frequency of clonality at any of 5 gene loci with the frequency of hypersensitivity to TPO of progenitor cells from the same female subjects in strictly serum-free megakaryocytic colony culture. The results are showing that among patients with a presumptive diagnosis of ET, it may be possible to identify a homogeneous population whose progenitor cells are both monoclonal and hypersensitive to TPO. The data also indicate that the assay method for TPO hypersensitivity might provide a reliable positive clinical diagnostic test for this ET patient population.
PV and ET were not the first clonal, chronic MPDs to show specific hypersensitivity of progenitor cells to normal endogenous cytokines that control proliferation, differentiation, and survival in their own cell lineages. In 1991 Emanuel et al in Alabama found that granulocyte/ macrophage (GM) progenitor cells in juvenile chronic myelogenous/myelomonocytic leukemia (JCML/JMML) were around 10 times as sensitive to the cytokine GM-CSF as normal progenitor cells in this lineage, while sensitivities to IL-3 and G-CSF remained unchanged. As one mechanism underlying the selective amplification of different progenitor cells in the different clonal chronic MPDs despite their origin in a single pluripotential stem cell, we now propose a lineage-restricted hypersensitivity of hematopoietic progenitor cells to normal endogenous cytokines. The clinicopathological phenotypes of the MPDs would thus be related to, and perhaps determined by, these specific cellular hypersensitivities.
The aims of my research program are to understand the cellular and molecular mechanism(s) underlying signal amplification processes responsible for hypersensitivity of progenitor cells to specific cytokines in each of the various MPDs, and their possible significance for malignant hematopoietic disease.
