The Transcriptional Landscape of B-Precursor Acute Lymphoblastic Leukemia: An International Collaborative Study of 1,223 Cases

Abstract

Background: B-cell precursor acute lymphoblastic leukemia (BCP ALL) represents a heterogeneous group of hematological malignancies. Although most classes can be classifiend into known major gene expression subtypes, a substantial proportion of BCP ALL remaines poorly characterized with regard to unclear underlying genomic abnormalities. We therefore initiated a large-scale international collaborative study to comprehensively reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA-seq-driven genomic analyses. Methods: RNA-seq data were collected from five BCP ALL cohorts, LUH (Sweden), MaSpore (Singapore and Malaysia), JALSG (Japan), M-HOPES/SIH (China) and TARGET/COG (USA). We performed gene expression based analyses to identify mRNA features in different subgroups and their association with distinct gene fusions/driver mutations. We also evaluated the prognosis of subgroups with adequate number of patients treated. Findings: Fourteen BCP ALL gene expression subgroups (G1-G14) were identified. Apart from extending eight previously described subgroups (G1-G8 associated with MEF2D fusions, TCF3-PBX1 fusions, ETV6-RUNX1/-like, DUX4 fusions, ZNF384 fusions, BCR-ABL1/Ph-like, hyperdiploidy and KMT2A fusions), we additionally defined six gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11, respectively, with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH-CEBPE fusion or mutations in ZEB2 (p.H1038R), and G13 and G14, respectively, with TCF3/4-HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2-G5 and G7 (51-65/67 chromosomes) displayed a low risk, G7 (with ≤50 chromosomes) and G9 showed an intermediate risk, whereas G1, G6 and G8 defined 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. Interpretation: Leukemogenic factors contributing to BCP ALL are highly heterogeneous. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete paths of BCP ALL, informing disease classification and prognostic stratification. Clinical Trial Information: Adult patients were enrolled in a SIH trial (Chinese Clinical Trial Registry, number ChiCTR-ONRC-14004968) which was basically a modification of the Vincristine, Daunorubicin, L‑ asparaginase, Cyclophosphamide and Prednisone (VDLCP) regimen. Pediatric patients in the Chinese cohort were enrolled in the Shanghai Children’s Medical Center ALL-2005 protocol (Chinese Clinical Trial Registry, number ONC-14005003) Funding Statement: This work was supported by Mega-Projects of Scientific Research for the 12th Five-Year Plan (2013ZX09303302); the National Natural Science Foundation of China (81570122, 81570122); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161303); the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (QD2015005); the National Key Research and Development Program (Grant 2016YFC0902800); Fine classification and standardized treatment of children with acute leukemia of multi center clinical research (14411950600) Shanghai Municipal Science and Technology Commission; Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development; U.S. National Institutes of Health Grants CA21765, CA36401, and U01 GM115279, and American Lebanese Syrian Associated Charities (ALSAC); The Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, and Governmental (ALF) Funding of Clinical Research within the Swedish National Health Service; NMRC/CSA/0053/2013; VIVA Foundation for Children with Cancer; Goh Foundation; Children's Cancer Foundation, Singapore Totalisator Board; the Samuel Waxman Cancer Research Foundation; the Center for HPC at Shanghai Jiao Tong University Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Ruijin hospital ethics committe gave approval for SIH trial.