Evi3, a common retroviral integration site in murine B-cell lymphoma, encodes an EBFAZ-related Krüppel-like zinc finger protein

Abstract

Retroviral insertional mutagenesis in inbred mouse strains provides a powerful method for cancer gene discovery. Here, we show that a common retroviral integration site (RIS) in AKXD B-cell lymphomas, termed Evi3, encodes a novel zinc finger protein with 30 Krü ppel-like zinc finger repeats. Most integrations at Evi3 are located upstream of the first translated exon and result in 3 long-terminal repeat (LTR)-driven overexpression of Evi3. Evi3 is highly related to the early B-cell factorassociated zinc finger gene (Ebfaz), and all 30 zinc fingers found in EVI3 are conserved in EBFAZ. EBFAZ binds to and negatively regulates early B-cell factor (EBF) (also known as olfactory-1, OLF1), a basic helix-loop-helix (bHLH) transcription factor required for B-lineage commitment and the development of the olfactory epithelium. EBFAZ also binds to SMAand MAD-related protein-1 (SMAD1) and SMAD4 in response to bone morphogenetic protein-2 (BMP2) signaling, which in turn activates the homeobox regulator of Xenopus mesoderm and neural development Xvent-2. Surprisingly, while Ebfaz and Evi3 are coexpressed in many tissues, and both proteins are nuclear, we could not detect Ebfaz expression in B cells by reverse transcriptase-polymerase chain reaction (RT-PCR), whereas Evi3 expression could be detected at all stages of B-cell development. Our results suggest that EVI3, like EBFAZ, is a multifunctional protein that participates in many signaling pathways via its multiple zinc fingers. Furthermore, our results suggest that EVI3, not EBFAZ, is the member of this protein family that interacts with and

DmOAZ, the unique Drosophila melanogaster OAZ homologue is involved in posterior spiracle development

“…We obtained 21% identity and 50% similarity (Fig. 1a), in spite of a reduced number of 21 ZF domains compared to the 29-30 ZFs present in vertebrates Reed 1997, 1998;Hata et al 2000;Warming et al 2003Warming et al , 2004. We also confirmed that DmOAZ is the unique OAZ member in the fruit fly.…”

“…The function of the ZF 1 was not yet characterized. By summarizing the different studies on OAZ family members, we noted that this organization was conserved Reed 1997, 1998;Hata et al 2000;Shim et al 2002;Ku et al 2003;Warming et al 2003Warming et al , 2004. To structurally analyze the DmOAZ protein, we determined the arrangement of the 21 ZFs in four clusters by using Simple Modular Architecture Research Tool software (http://smart.embl-heidelberg.de; Schultz et al 1998;Letunic et al 2004), and we aligned each DmOAZ cluster on the entire sequence of the orthologues.…”

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

“…Zfp521 was originally identified as a retroviral integration site in AKXD mice with B-lineage lymphomas, which encodes a transcription factor with multiple zinc-fingers (Warming et al, 2003). Although the molecular mechanisms by which aberrant expression of Zfp521 contributes to leukemogenesis are not fully understood, one possibility is that Zfp521 impairs normal B-cell development by inhibiting the function of EBF1 (Hentges et al, 2005), a transcription factor required for B-cell development (Lin and Grosschedl, 1995).…”

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

“…Three translocations were identified (PAX5-ETV6, 56,57 PAX5-FOXP1, PAX5-ZNF521), each of which fuses the DNA-binding paired domain of PAX5 to key functional domains of partner genes that have known or putative roles in lymphoid development or oncogenesis. [58][59][60][61][62] These translocations are predicted to disrupt normal activity of PAX5 (and possibly the partner gene), and in luciferase reporter assays using a CD19 reporter, the fusions were found to act as competitive inhibitors of normal PAX5 transactivating activity. Subsequent studies have identified additional PAX5 fusions in ALL, involving multiple partner genes including ASXL1, AUTS2, BRD1, C20orf112, DACH1, ELN, HIPK1, JAK2, KIF3B, LOC392027, PML, POM121 and SLCO1B3.…”