A novel class of ZNF384 aberrations in acute leukemia

Abstract

Fusion of the ZNF384 gene as the 3' partner to several different 5' partner genes occurs recurrently in B-cell precursor acute lymphoblastic and mixed phenotype B/myeloid leukemia. These canonical fusions (ZNF384r) contain the complete ZNF384 coding sequence and are associated with a specific gene expression signature. Cases with this signature, but without canonical ZNF384 fusions (ZNF384r-like cases), have been described previously. Although some have been shown to harbor ZNF362 fusions, the primary aberrations remain unknown in a major proportion. We studied 3 patients with the ZNF384r signature and unknown primary genetic background and identified a previously unknown class of genetic aberration affecting the last exon of ZNF384 and resulting in disruption of the C-terminal portion of the ZNF384 protein. Importantly, in 2 cases, the ZNF384 aberration, indel, was missed during the bioinformatic analysis but revealed by the manual, targeted reanalysis. Two cases with the novel aberrations had a mixed (B/myeloid) immunophenotype commonly associated with canonical ZNF384 fusions. In conclusion, we present leukemia cases with a novel class of ZNF384 aberrations that phenocopy leukemia with ZNF384r. Therefore, we show that part of the so-called ZNF384r-like cases represent the same genetic subtype as leukemia with canonical ZNF384 fusions.

Figure 1.

Hierarchical clustering and schematic representation of ZNF384 proteins. (A) Hierarchical clustering based on RNA-seq gene-expression data. A total of 117 B-other, 9 ETV6-RUNX1–positive, and 2 BCR-ABL1–positive ALL/MPAL cases were clustered hierarchically (vst normalization, ward.D method, and Euclidean distance linkage for hierarchical clustering) based on the expression of the most variably expressed transcripts (transcripts with standard deviation of expression ≥35% of the maximal standard deviation; n = 391). The resulting dendrogram is shown. ALL was classified as BCR-ABL1-like and ETV6-RUNX1-like based on coclustering with BCR-ABL1–positive and ETV6-RUNX1–positive ALL, respectively, in supervised HCA. Classification into genetically defined subtypes was based on the identification of defining genetic lesions. The cohort consists of 110 patients as reported previously, complemented by 7 additional patients with ZNF384 gene aberrations and available RNA-seq data. B-rest, not classified into any established subtype; iamp, intrachromosomal amplification; AMP, amplification. (B) Schematic representation of the wild-type ZNF384 protein with the positions of 3 novel aberrations and chimeric proteins encoded by canonical ZNF384 fusion and the novel ZNF384-TEX41 fusion. LZ, leucine-rich domain; NLS, nuclear localization signal; PR, proline-rich domain; QA, Gln-Ala repeat; SR, serine-rich domain; ZFs, Kruppel-type C2H2 zinc-finger domains. Adapted from Liu et al with permission.