Dysregulation of metallothionein MT1 sub-types in TCF3::PBX1 pre-B-cell acute lymphoblastic leukemia

Abstract

The translocation between chromosomes 1 and 19 t(1;19) produces the TCF3::PBX1 fusion protein, which leads to childhood pre-B-cell acute lymphoblastic leukemia (ALL). The molecular mechanism of oncogenesis, however, remains obscure. This study aims to identify the genes specifically dysregulated in TCF3::PBX1 translocation. The publicly available expression microarray datasets on ALL were used for weighted gene co-expression network analysis (WGCNA) to identify modules associated with TCF3::PBX1. The available knockdown and ChIP-Seq datasets were used to assess the direct targets of TCF3::PBX1. The WGCNA revealed a module enriched in genes involved in the metal ion stress to be positively correlated with TCF3::PBX1, with metallothionein isoform MT1 subtypes MT1E, MT1F, MT1G, MT1H, and MT1X as the hub genes. Of the 145 positively correlated genes, 19 were downregulated upon TCF3::PBX1 knockdown. Eleven of these 19 genes including MT1G, showed TCF3::PBX1 occupancy at the promoter. The Metallothionein 1 family has been implicated in various cancers; however, their role in t(1;19) pre-B-cell ALL has not been previously demonstrated. Our analysis effectively accounts for the cellular and population-level heterogeneity and identifies a novel mechanism for the TCF3::PBX1 action.