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

Significance In BCP ALL, molecular classification is used for risk stratification and influences treatment strategies. We reanalyzed the transcriptomic landscape of 1,223 BCP ALLs and identified 14 subgroups based on their transcriptional profiles. Eight of these (G1 to G8) are previously well-known subgroups, harboring specific genetic abnormalities. The sample size allowed the identification of six previously undescribed subgroups, consisting of cases harboring PAX5 or CRLF2 fusions (G9), PAX5 (p.P80R) mutations (G10), IKZF1 (p.N159Y) mutations (G11), either ZEB2 (p.H1038R) mutations or IGH–CEBPE fusions (G12), HLF rearrangements (G13), or NUTM rearrangements (G14). In addition, this study allowed us to determine the prognostic impact of several recently defined subgroups. This study suggests that RNA sequencing should be a valuable tool in the routine diagnostic workup for ALL. 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 MEF2D fusions, TCF3–PBX1 fusions, ETV6–RUNX1–positive/ETV6–RUNX1–like, DUX4 fusions, ZNF384 fusions, BCR–ABL1/Ph–like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH–CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4–HLF and NUTM1 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.

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