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

Abstract

Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP. ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300-and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.

Myeloid lineage switch following chimeric antigen receptor T‐cell therapy in a patient with TCF3‐ZNF384 fusion‐positive B‐lymphoblastic leukemia

“…CMA results were remarkable for a 12p13 deletion with a breakpoint within the ZNF384 gene, suggesting the presence of a ZNF384 fusion (Table ). Testing with a custom next‐generation sequencing (NGS) based panel (OncoKids™) revealed the presence of a TCF3‐ZNF384 fusion (Figure ) and an internal tandem duplication in the FLT3 gene. To determine if the TCF3‐ZNF384 fusion was present in the patient's B‐ALL, RT‐PCR and Sanger sequencing were performed using RNA from an FFPE clot sample from the BM aspirate obtained at the time of the CD19‐positive relapse after the first HSCT.…”

Emerging entities in NUTM1‐rearranged neoplasms

“…ACIN1‐NUTM1 fusions have now also been reported on several more occasions in infant and pediatric ALLs . Other NUTM1 fusion partners reported in ALL are IKZF1 , ZNF618 , AFF1 , SLC12A6 , CUX1 , and BPTF …”

Cryptic recurrent ACIN1‐NUTM1 fusions in non‐KMT2A‐rearranged infant acute lymphoblastic leukemia

“…Thirteen patients were identified with eight different fusion partners always located at the 5 0 portion of the fusion product (Table S5). 7,9,[13][14][15][16][17] Two infant BCP-ALL were identified harboring either ACIN1-NUTM1 or BRD9-NUTM1 fusions. 9 These findings suggest that genetic rearrangements of NUTM1 with various fusion partners may be recurrent events in infant BCP-ALL, as reported in pediatric BCP-ALL.…”