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

Li, Jian Feng; Dai, Yu Ting; Lilljebjörn, Henrik LU ; Shen, Shu Hong; Cui, Bo Wen; Bai, Ling; Liu, Yuan Fang; Qian, Mao Xiang; Kubota, Yasuo and Kiyoi, Hitoshi, et al. (2018) In Proceedings of the National Academy of Sciences of the United States of America 115(50). p.11711-11720
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 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... (More)

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. four decades, most of the recurring chromosomal abnormalities, including aneuploidy, chromosomal rearrangements/gene fusions (e.g., ETV6–RUNX1, BCR–ABL1, and TCF3–PBX1), and rearrangements of KMT2A (previously MLL), were identified by.

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keywords
BCP ALL, Gene fusion, Gene mutation, RNA-seq, Subtypes
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Proceedings of the National Academy of Sciences of the United States of America
volume
115
issue
50
pages
11711 - 11720
publisher
National Acad Sciences
external identifiers
  • scopus:85058446665
ISSN
0027-8424
DOI
10.1073/pnas.1814397115
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English
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yes
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26dd769e-7441-41b5-8b35-a9ee3b58942e
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2019-01-03 12:54:14
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@article{26dd769e-7441-41b5-8b35-a9ee3b58942e,
  abstract     = {<p>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. four decades, most of the recurring chromosomal abnormalities, including aneuploidy, chromosomal rearrangements/gene fusions (e.g., ETV6–RUNX1, BCR–ABL1, and TCF3–PBX1), and rearrangements of KMT2A (previously MLL), were identified by.</p>},
  author       = {Li, Jian Feng and Dai, Yu Ting and Lilljebjörn, Henrik and Shen, Shu Hong and Cui, Bo Wen and Bai, Ling and Liu, Yuan Fang and Qian, Mao Xiang and Kubota, Yasuo and Kiyoi, Hitoshi and Matsumura, Itaru and Miyazaki, Yasushi and Olsson, Linda and Tan, Ah Moy and Ariffin, Hany and Chen, Jing and Takita, Junko and Yasuda, Takahiko and Mano, Hiroyuki and Johansson, Bertil and Yang, Jun J. and Yeoh, Allen Eng Juh and Hayakawa, Fumihiko and Chen, Zhu and Pui, Ching Hon and Fioretos, Thoas and Chen, Sai Juan and Huang, Jin Yan},
  issn         = {0027-8424},
  keyword      = {BCP ALL,Gene fusion,Gene mutation,RNA-seq,Subtypes},
  language     = {eng},
  number       = {50},
  pages        = {11711--11720},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases},
  url          = {http://dx.doi.org/10.1073/pnas.1814397115},
  volume       = {115},
  year         = {2018},
}