Identification of novel Runx1 (AML1) translocation partner genes SH3D19, YTHDf2, and ZNF687 in acute myeloid leukemia

Abstract

Three patients diagnosed with acute myeloid leukemia (AML) with reciprocal 21q22/RUNX1(AML1) translocations involving chromosomes 1 and 4 were studied. Three novel RUNX1 translocation partner genes on 1q21.2 (ZNF687), 1p35 (YTHDF2), and 4q31.3 (SH3D19) were identified using a panhandle polymerase chain reaction and the 3' rapid amplification of cDNA ends method. The translocation events occurred between exons 3 and 7 of the RUNX1 gene. The partner gene breakpoints localized to the region in the partner gene with the highest Alu density, suggesting that Alus may contribute to the recombination events. Two out of three of the cases retained RUNX1's entire RUNT domain in the translocation, and RUNX1 mutations were absent in the fusion transcripts, confirmed by reverse transcription-polymerase chain reaction and sequencing analysis. SH3D19 encodes a cytoplasmic protein EBP known to suppress RAS-induced cellular transformation, which can be inhibited by nuclear recruitment. The t(4;21) created a hybrid RUNX1-EBP protein retaining RUNX1's DNA binding domain, which may result in nuclear localization of the chimeric protein and inhibition of EBP's RAS-suppressive functions. Future studies would be useful to further characterize these novel fusion protein products.

Fusion gene‐mediated truncation of RUNX1 as a potential mechanism underlying disease progression in the 8p11 myeloproliferative syndrome

“…(16q24), and PRDX4 (Xp22) (Mitelman et al, 2007). In all these fusions, with the exception of ZNF687, the runt homology domain (RHD) of RUNX1, encoded by exons 3-5, remains intact (Erickson et al, 1992;Nucifora et al, 1993Nucifora et al, , 1994Mitani et al, 1994;Gamou et al, 1998;Ramsey et al, 2003;Zhang et al, 2004;Nguyen et al, 2006;Paulsson et al, 2006;Stevens-Kroef et al, 2006). The 128 aa RHD is crucial both for DNA binding and for heterodimerization with CBFB, which increases the DNA affinity of RUNX1 by stabilizing its conformation (Kim et al, 1999) and protects RUNX1 from ubiquitin-proteasome mediated degradation (Huang et al, 2001).…”

Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine

“…Two recent studies show that YTH domain family 2 (YTHDF2) and other YTHDF proteins preferentially bind to m 6 A-containing mRNA in vivo and in vitro and regulate localization and stability of the bound mRNA [8,11]. YTHDF2 is also known to be involved in development of acute myeloid leukemia [12]. YTHDC1 (splicing factor YT521-B), another YTH domain-containing protein, is known to play an important role in Emery-Dreifuss muscular dystrophy.…”

Anticancer Activity and Differentially Expressed Genes in Head and Neck Cancer Cells Treated with a Novel Cyclin-Dependent Kinase Inhibitor

“…Interestingly, the expression of Repin1 in the liver has been shown to be significantly associated with the repeat size of the 3 -untranslated region, and the triplet repeat expansion in the 3 -untranslated region is involved in metabolic alterations as found in hHTg and WOKW rats, thus suggesting that Repin1 may be a novel candidate gene for the development of facets of the metabolic syndrome [48] . YTH domain family member 2 (YTHDF2) is thought to be involved in the humoral immune response [49] . YTHDF2 is expressed in a wide variety of organs but mainly in testis, placenta and pancreas, and its expression is regulated by high glucose concentrations [50] .…”