Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases

Abstract

Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with <i>MEF2D</i> fusions, <i>TCF3-PBX1</i> fusions, <i>ETV6-RUNX1</i>-positive/<i>ETV6-RUNX1</i>-like, <i>DUX4</i> fusions, <i>ZNF384</i> fusions, <i>BCR-ABL1</i>/Ph-like, high hyperdiploidy, and <i>KMT2A</i> fusions), we defined six additional gene expression subgroups: G9 was associated with both <i>PAX5</i> and <i>CRLF2</i> fusions; G10 and G11 with mutations in <i>PAX5</i> (p.P80R) and <i>IKZF1</i> (p.N159Y), respectively; G12 with <i>IGH-CEBPE</i> fusion and mutations in <i>ZEB2</i> (p.H1038R); and G13 and G14 with <i>TCF3/4-HLF</i> and <i>NUTM1</i> fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.