PV Progenitors and Signal Transduction

In 1974 Prchal and Axelrad39 reported the key observation that cultures of PV bone marrow cells yielded in vitro erythroid colonies even when no exogenous erythropoietin was added to the culture media. These have been termed endogenous ery-throid colonies (EEC) or erythropoietin-independent burst forming unit erythroid (BFU-E) but the mechanisms responsible for their formation remain obscure. Growth of BFU-E in the absence of added erythropoietin may reflect complete independence of this cytokine40 or hypersensitivity to trace amounts present in the culture reagents.41 In serum-free systems erythropoietin-independent colonies are seen in normal individuals, raising the possibility that BFU-E from PV patients have a reduced sensitivity to an inhibitory factor present in serum.42 In spite of this biological complexity two conclusions can be drawn from recent studies of PV progenitors. First, ery-throid progenitors have been shown to be hypersensitive to several different growth factors including SCF, interleukin (IL)-3, GM-CSF, and IGF-1.43-45 Second, myeloid progenitors (CFU-Meg and CFU-GM) also show abnormal patterns of growth.43,46,47 These findings are consistent with a model in which the acquired genetic lesion in PV is not restricted to the erythropoietin-signaling pathway and affects progenitors committed to multiple lineages (Figure 9-1).

A number of signal transduction molecules have been studied as potential PV target genes. Initial attention focused on the erythropoietin receptor (Epo-R). Experimentally induced mutations in the Epo-R result in hypersensitivity to, or independence of, exogenous erythropoietin. Truncation of the cyto-plasmic domain of the Epo-R, leading to hypersensitivity to Epo, has been found in primary familial polycythemia48 and confirmed in several other cases of congenital polycythemia, occasionally occurring sporadically.49-51 Several groups have therefore looked at the integrity of the Epo-R gene in bone marrow cells from PV patients but none have detected muta-tions.52,53 Decreased expression of a shortened Epo-R isoform encoded by an alternate transcript has been implicated in PV54 but similar alternate splicing events in solid tumors have not been shown to play a causal role in tumor pathogenesis.55

Figure 9-1. Possible defects in signal transduction in myeloproliferative disorder (MPD). Progenitor cells from patients are hypersensitive to a number of cytokines (A and B) such as EPO, which act through specific receptor molecules (C and D). There may be a defect in a common receptor component (E), a common signalling intermediate (F), or a common effector molecule (G) such as a transcription factor. (From Hinshelwood et al.,32 with permission.)

The reported hypersensitivity of PV progenitor cells to multiple cytokines raised the possibility of a defect in a downstream signaling pathway common to multiple different cytokine receptors (Figure 9-1). The tyrosine phosphatase SHP-1 (also known as HCP) was considered a prime candidate as it inhibits signaling from Epo-R and other cytokine receptors, and hematopoietic progenitors carrying a null mutation in SHP-1 are hypersensitive to cytokines. However, SHP-1 protein expression was normal in granulocytes from PV patients and complete nucleotide sequencing of the SHP-1 coding region and promoter in eight patients showed no mutations.56 These results do not exclude a role for other inhibitory phosphatases and a novel protein with increased phosphatase activity has been reported in PV progenitors.57

In addition to the Epo-R, a number of other cytokine receptors have been studied. Axelrad and co-workers have looked at tyrosine phosphorylation of the IGF-1 receptor subunit in the peripheral blood mononuclear cells from PV patients. They detected a higher basal level of phosphorylation of this receptor and enhanced downstream signaling as judged by increased tyrosine phosphorylation following stimulation with IGF-1.58 The thrombopoietin receptor c-mpl, present on mutilineage progenitors as well as megakaryocytes and platelets is also an attractive candidate. Spivak and others have reported a reduced expression of c-mpl on platelets and megakaryocytes from patients with PV.59 This finding may distinguish PV from secondary polycythemia60,61 but not other MPDs.62,63 A report has suggested that a marked heterogeneity exists in c-mpl protein levels in PV and this question currently limits its use as a diagnostic test.64 An increase in certain splice variants and glycosylated forms of the c-mpl receptor have also been found with the degree of glycosylation suggested to correlate with the duration of disease and, possibly, with progression to myelofibrosis.65,66 It has also been suggested that reduced apoptosis may be important in PV since an increase in Bcl-xL was reported in ery-throid cells from PV patients.67 However, as with other reports of genes differentially expressed in normal and PV cells, such as the uPAR receptor superfamily member PRV-1,68 the patho-genetic significance of these observations remains unclear.

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