A novel recurrent EP300–ZNF384 gene fusion in B-cell precursor acute lymphoblastic leukemia

Abstract

CT designed the research, analyzed the data and wrote the paper; IS supervised the work; PVR, SC, RP and CDB performed experiments; GZ provided AML cell lines, reagents and analyzed the data; SC and DB commented on the paper. SC and RF provided AML samples. AA provided TALL samples. CT, PVR, SC assembled the figures. AUTHOR CONTRIBUTIONS CT designed the research, analyzed the data and wrote the paper; IS supervised the work; PVR, SC, RP and CDB performed experiments; GZ provided AML cell lines, reagents and analyzed the data; SC and DB commented on the paper. SC and RF provided AML samples. AA provided TALL samples. CT, PVR, SC assembled the figures.

ZNF384 -related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype

“…[9][10] In addition to those previously reported ZNF384-related fusion genes, we identified EP300-ZNF384, t (12;22), as a novel recurrent fusion gene with an incidence of approximately 1% in B-others in a Japanese cohort. 11 The recurrence of EP300-ZNF384 in pediatric BCP-ALL patients as well as a higher incidence in adolescent and young adult (AYA) BCP-ALL patients was confirmed by other groups. [12][13][14][15] Furthermore, the CREB binding protein gene {CREBBP, t(12;16)(p13;p13)} has been most recently identified as another novel fusion partner for ZNF384.…”

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

“…While ZNF384 rearrangement is predominantly observed in B-ALL, these leukemia blast cells also often express myeloid markers (La Starza et al 2005;Gocho et al 2015;Ping et al 2015), pointing to its possible link to biphenotypic leukemia. Clinically, ZNF384-rearranged ALLs do not exhibit other unique presenting features and tend to be associated with a favorable prognosis in retrospective studies.…”

“…We postulate that the juxtaposition of the partner gene with ZNF384 in the fusion protein confers novel functions that may interfere with normal hematopoiesis at multiple stages. So far, five partner genes (EP300, CREBBP, TAF15, TCF3, and ESWR1) (Martini et al 2002;Zhong et al 2008;Nyquist et al 2011;Gocho et al 2015) have been identified in ZNF384-rearranged ALL, and it remains unclear whether there is a common mechanism for leukemogenesis in these cases. Our preliminary data thus far indicated that at least the TAF15-and TCF3-ZNF384 fusions also positively regulated BTLA and CLCF1 transcription and potentiated oncogenic transforming effects in Ba/f3 cells (especially with CRLF2), although with distinctive effects on HSPC function in vitro compared with EP300-and CREBBP-ZNF384 fusions (Supplemental Figs.…”

“…Mutations in histone genes themselves (e.g., histone gene cluster on 6p22) (Mullighan et al 2007), histone modifying enzymes (e.g., SETD2, ASXL2, KMT2D, KDM6A) (Huether et al 2014;Mar et al 2014;Zhu et al 2014), and chromatin remodeling genes (e.g., ASXL1, EZH2) (Nikoloski et al 2010;Balasubramani et al 2015) have also been reported, albeit with low frequencies. More recently, EP300 fusion with the transcription factor ZNF384 has been reported in ALL (Gocho et al 2015;Ping et al 2015;Yasuda et al 2016), and ZNF384 is also implicated in chromosomal translocation with a number of partner genes (Martini et al 2002;La Starza et al 2005;Zhong et al 2008;Nyquist et al 2011;Yasuda et al 2016), although the biological functions of these fusions are largely unknown.…”

PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia

“…4 Recently, the recurrence of a novel fusion gene, EP300-ZNF384, was first detected using RNA-sequencing and subsequently screened for by RT-PCR. 15 By combining RNA-sequencing with copy number analysis data from high-density single nucleotide polymorphism arrays and Human Methylation 450 Bead Chips, we identified a group of rare cases harboring the same gene fusion within a large ALL cohort, in which screening by RT-PCR would not be feasible. While genotyping arrays can be useful in screening for unbalanced rearrangements, such as the der(9)t(9;14), they are not suitable for the detection of balanced rearrangements.…”