1q22

Acute lymphoblastic leukemia (ALL)

A variant t(1;19)(q23;p13.3) 1048 translocation creates reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1 fusion genes that are expressed in acute lymphoblastic leukemia (ALL).
DAZAP1 is expressed most abundantly in the testis and mapped to 19p13.3. DAZAP1 is fused to MEF2D by the t(1;19); the genomic breakpoints occur in introns of MEF2D and DAZAP1 (der(1) (Genbank accession AY681493) and der(19) (accession AY681494)). der(19) breakpoint is located within the 1500 kilobases (kb) of DNA telomeric to E2A. Rearrangments are seen only in TS-2 (ALL cell line) establishing that the t(1;19) interrupts the 19p13.3 gene DAZAP1 with the breakpoint region in approximately the middle of the gene. There is a 5 base pairs insertion at the site of genomic fusion on the der(19) that is not derived from either germline chromosome 1 or 19. Homologous breakpoints occur on the der(1) chromosome with a deletion of 97 bp and a 21 bp GC-rich insertion. MEF2D/DAZAP1 and DAZAP1/MEF2D fusion transcripts are expressed in-frame in TS-2 cells in addition to wild-type DAZAP1 and MEF2D transcripts (Prima et al., 2005).

In-frame MEF2D/DAZAP1 and DAZAP1/MEF2D fusion transcripts are expressed in TS-2 cell line and define the DNA-, RNA-binding, and transcriptional regulatory properties of the resultant chimeric proteins. Native DAZAP1 (NP_061832) includes two identified RNA recognition motifs (RRM) specified by amino acids 1-87 and 105-190. DAZAP1/MEF2D fusion cDNAs (accession AY678451) are predicted to encode a chimeric protein that contains all of the first DAZAP1 RRM and a truncated portion of the second RRM joined to the carboxy terminal portion of MEF2D that includes the second TAD. Reciprocal MEF2D/DAZAP1 fusion transcripts (accession AY675556) are predicted to encode a chimera that includes the MEF2D MADS-box, MEF2 domain, and the first TAD joined to the carboxy terminus of DAZAP1 including a truncated portion of RRM 2. DAZAP1 bound strongly to poly(U) and poly(G) at 0.1 M NaCl, whereas DAZAP1/MEF2D bound to the same homopolymers to a lesser degree; MEF2D/DAZAP1 retains DNA-binding properties of wild type MEF2D; MEF2D/DAZAP1 is a more potent transcriptional activator than wild type MEF2D. MEF2D-DAZAP1 was co-immunoprecipitated with wild type MEF2D from HEK293 cells, suggesting that the wild type and chimeric MEF2D proteins could form heterodimers and/or associate with one another in a higher order protein complex in vivo. (Yuki et al., 2004).

MEF2D and DAZAP1 fusion proteins were identified as components of novel pathways that contribute to human leukemogenesis. Both MEF2D/DAZAP1 and DAZAP1/MEF2D have oncogenic properties, and co-expression of both fusion proteins is synergistic (Prima and Hunger, 2007).
MEF2D/DAZAP1 might directly activate transcription of genes critical for lymphocyte growth and/or survival such as interleukin-2, a known transcriptional target of MEF2D in T-cells. Alternatively, MEF2D/DAZAP1 could contribute to leukemogenesis via dysregulated activation of MAPK-mediated cell proliferation pathways, analogous to constitutive activation of a growth factor receptor.