Abstract
Hematological malignancies in humans typically involve two types of genetic changes: those that promote hematopoietic cell proliferation and survival (often the result of activation of tyrosine kinases) and those that impair hematopoietic cell differentiation (often the result of changes in transcription factors). The multi-stage erythroleukemia induced in mice by Friend spleen focus-forming virus (SFFV) is an excellent animal model for studying the molecular basis for both of these changes. Significant progress has been made in understanding the molecular basis for the multi-stage erythroleukemia induced by Friend SFFV. In the first stage of leukemia, the envelope protein encoded by SFFV interacts with and activates the erythropoietin (Epo) receptor and the receptor tyrosine kinase sf-Stk in erythroid cells, causing their Epo-independent proliferation, differentiation and survival. In the second stage, SFFV integration into the Sfpi1 locus activates the myeloid transcription factor PU.1, blocking erythroid cell differentiation, and in conjunction with the loss of p53 tumor suppressor activity, results in the outgrowth of malignant cells. In this review, we discuss the current level of understanding of how SFFV alters the growth and differentiation of erythroid cells and results in the development of erythroleukemia. Our knowledge of how SFFV causes erythroleukemia in mice may give us clues as to how the highly related human retrovirus XMRV causes malignancies in humans.
Highlights
Fifty-three years ago, Charlotte Friend described an acute erythroleukemia induced in adult Swiss mice by a viral preparation that subsequently became known as Friend virus [1]
It was later shown that this virus preparation contained two retroviruses: (1) a defective spleen focus-forming virus (SFFV), which is responsible for the acute erythroleukemia that occurs in adult mice, and (2) a replication competent Friend murine leukemia virus (F-MuLV), which is not pathogenic by itself in adult mice, but serves as a helper to allow the defective SFFV to infect and integrate into cells
By virtue of its requirement to activate SFFV-induced Epo-independent signaling in erythroid cells and erythroleukemia in mice, short form Stk (sf-Stk) became a likely candidate to mediate the activation of signal transduction pathways by SFFV, and subsequent studies focused on confirming this hypothesis
Summary
Fifty-three years ago, Charlotte Friend described an acute erythroleukemia induced in adult Swiss mice by a viral preparation that subsequently became known as Friend virus [1]. The SFFV envelope gene is closely related to that of the polytropic Friend mink cell focus-inducing MuLV, it contains several changes that are responsible for its unique biological effects (Figure 1) [4,5,6]. First of all, it contains a large deletion in the open reading frame of the gene that eliminates a proteolytic cleavage site where the envelope protein precursor of a typical MuLV is cleaved into surface unit (SU). The cell surface form of the SFFV envelope protein appears to mediate the biological effects of the virus [15,16,17]
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