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Letters to the Editor
Frequency and prognostic impact of ZEB2 H1038 and Q1072 mutations in childhood B-other acute lymphoblastic leukemia
In order to identify novel prognostic markers and actionable targets, we performed whole-exome/-tran- scriptome sequencing of relapsed childhood B-cell pre- cursor (BCP) acute lymphoblastic leukemia (ALL) diag- nosed in the Czech Republic. In patients with “B-other ALL” (BCP-ALL negative for ETV6-RUNX1, BCR-ABL1, TCF3-PBX1, and KMT2A rearrangement, hyperdiploidy [51-67 chromosomes] and hypodiploidy [<44 chromo- somes]), we found recurrent mutations of codons H1038 and Q1072 of the zinc finger E-box binding homeobox 2 (ZEB2) gene. The ZEB2 gene is located on 2q22.3 and encodes a transcriptional repressor implicated in the pathogenesis of early T-cell ALL, possibly via deregula- tion of IL7R-JAK/STAT signaling.1,2 It is known that codons H1038 and Q1072 are located in the C-terminal zinc finger coding-region (DNA binding region), but the impact of the mutations (ZEB2mut) on ZEB function is unknown. Although recurrence of ZEB2mut in BCP-ALL is being traced in a growing number of genomic studies,3- 6 the biological and clinical roles of these mutations in BCP-ALL have not been described so far.
In this study, we aimed to determine the frequency and clinical relevance of ZEB2mut in childhood B-other ALL. Using whole-exome sequencing, RNA-sequencing and amplicon sequencing of DNA or complementary DNA
(cDNA), we analyzed 231 and 36 Czech children with newly manifesting and relapsed B-other ALL, respective- ly (the so-called “discovery cohorts”), consecutively diag- nosed between November 2002 and December 2017 and treated according to several successive Berlin-Frankfurt- Münster (BFM)-based protocols (see Online Supplementary Data). We detected ZEB2mut in 3.8% (9/231) of newly diagnosed B-other ALL. ZEB2mut was associated with significantly worse event-free survival and a higher relapse rate (Figure 1A and B). In accordance with the higher relapse rate, we found significant enrichment of ZEB2mut in the discovery relapse cohort (8/36, 29%; P=0.0005). Interestingly, two out of the total nine relaps- es were isolated extramedullary relapses and one was a combined extramedullary and bone marrow relapse.
To validate these findings, we analyzed 626 and 102 children with newly diagnosed and relapsed B-other ALL diagnosed and treated in Germany (the so-called “valida- tion cohorts”). The frequency of ZEB2mut in the valida- tion cohort of newly manifesting leukemias (enrolled into the Associazione Italiana di Ematologia e Oncologia Pediatrica [AIEOP]-BFM ALL 2000 and 2009 protocols) was 2.7% (17/626). While ZEB2mut was associated with a significantly higher relapse frequency in the patients enrolled into the AIEOP-BFM ALL 2000 study (Figure 1C and D), only 1/12 ZEB2mut patients enrolled in the AIEOP-BFM ALL 2009 study relapsed and two patients died without relapse. In the validation relapse cohort, ZEB2mut frequency was 4.9% (5/102), which was signif-
AB
CD
Figure 1. Outcome analysis. (A-D) Event-free survival and cumulative incidence of relapse at 5 years according to ZEB2mut status in patients with newly diag- nosed B-other acute lymphocytic leukemia in the discovery cohort (A, B) and those from the validation cohort who were treated on the AIEOP-BFM ALL 2000 protocol (C,D). SE: standard error.
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haematologica | 2021; 106(3)