t(1;19)(q22;p13.2) MEF2D/DAZAP1

2019-05-01   Tatiana Gindina 

1.R.M. Gorbacheva Memorial Institute of Children Oncology Hematology and Transplantation at First Pavlov Saint-Petersburg State Medical University, Saint-Petersburg, Russia / tatgindina@gmail.com

Abstract

Review on t(1;19)(q22;p13.2) MEF2D/DAZAP1, with data on the genes involved

Clinics and Pathology

Disease

B lymphoblastic leukemia

Epidemiology

Only one case to date: a 3-year-old female child (Yuki et al., 2004; Prima et al., 2005; Liu et al., 2016).

Genes Involved and Proteins

Gene name
MEF2D (Myocyte Enhancer Factor 2D)
Location
1q22
Protein description
MEF2D belongs to the MADS-box family of transcription factors; this molecule binds as a homo- or hetero-dimer to the MEF2 element present in the regulatory regions of numerous muscle-specific and growth-factor and stress-induced genes. A remarkable increase in expression levels of MEF2A and MEF2D has been reported during differentiation into monocytes using the promyeloid HL-60 cell line (Yuki et al., 2004). In mouse models, MEF2D was identified as a candidate oncogene involved in the pathogenesis of leukemia. It is assumed, that native MEF2D has latent transforming properties, which can be unmasked via aberrant protein expression (Prima et al., 2005).
Gene name
DAZAP1 (Deleted in Azoospermia-Associated Protein 1)
Location
19p13.3
Protein description
DAZAP1 is an RNA binding protein, which contains two RNA-recognition motifs (RRMs), a proline-rich C-terminal portion and expressed most abundantly in the testis during spermatogenesis, and to a lower level, in the thymus.

Result of the Chromosomal Anomaly

Description

The genes were fused in-frame between exon 6 of MEF2D and exon 7 of DAZAP1 (MEF2D/DAZAP1), as well as, between exon 6 of DAZAP1 and exon 7 of MEF2D (DAZAP1/MEF2D). Sequencing of the RT-PCR products confirmed in-frame fusions between MEF2D (codon 222) and DAZAP1 (codon 155) in both chimeric transcripts (Yuki et al., 2004).

Transcript

Both chimeric transcripts, MEF2D/DAZAP1 and DAZAP1/MEF2D, whose sequences indicated in-frame fusions between MEF2D and DAZAP1 were expressed in bone marrow cells (Yuki et al., 2004).
Atlas Image
Schematic representation of the wild-type MEF2D and DAZAP1 products and of the chimeric fusion proteins MEF2D/DAZAP1 and DAZAP1/MEF2D.

Expression localisation

MEF2D/DAZAP1 and DAZAP1/MEF2D proteins were both located in the nucleus, MEF2D/DAZAP1 was able to form dimers with MEF2D and HDAC4. Furthermore, exogenous expression of MEF2D/DAZAP1 and DAZAP1/MEF2D promoted the growth of HeLa cells (Yuki et al., 2004).

Oncogenesis

MEF2D/DAZAP1 and/or DAZAP1/MEF2D contribute to leukemogenesis by altering signaling pathways normally regulated by wild-type MEF2D and DAZAP1. MEF2D/DAZAP1 binds avidly and specifically to DNA and is a substantially more potent transcriptional activator, than MEF2D and also may associate more strongly with other proteins involved in transcriptional regulation (e.g. HDAC4). MEF2D/DAZAP1 might immediately activate transcription of genes crucial for lymphocyte growth and/or survival such as IL2 (interleukin-2), a known transcriptional target of MEF2D in T-cells. As well, MEF2D/DAZAP1 could contribute to leukemogenesis via dysregulated activation of MAPK-mediated cell proliferation pathways. These alterations may confer more potent transforming properties to MEF2D/DAZAP1, which can be further augmented by coexpression with the reciprocal DAZAP1/MEF2D chimera, which retains sequence-specific RNA binding properties (Prima et al., 2005).

Bibliography

Pubmed IDLast YearTitleAuthors
274284282016Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia.Liu YF et al
157443502005Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia.Prima V et al
151824312004Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t(1;19)(q23;p13).Yuki Y et al

Summary

Fusion gene

MEF2D/DAZAP1

Citation

Tatiana Gindina

t(1;19)(q22;p13.2) MEF2D/DAZAP1

Atlas Genet Cytogenet Oncol Haematol. 2019-05-01

Online version: http://atlasgeneticsoncology.org/haematological/1843/t(1;19)(q22;p13-2)

External Links