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Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

Author

Listed:
  • Tomoya Isobe

    (The University of Tokyo
    The University of Tokyo
    University of Cambridge)

  • Masatoshi Takagi

    (Tokyo Medical and Dental University)

  • Aiko Sato-Otsubo

    (The University of Tokyo)

  • Akira Nishimura

    (Tokyo Medical and Dental University)

  • Genta Nagae

    (The University of Tokyo)

  • Chika Yamagishi

    (Tokyo Medical and Dental University)

  • Moe Tamura

    (The University of Tokyo)

  • Yosuke Tanaka

    (The University of Tokyo)

  • Shuhei Asada

    (The University of Tokyo
    Tokyo Women’s Medical University)

  • Reina Takeda

    (The University of Tokyo)

  • Akiho Tsuchiya

    (The University of Tokyo)

  • Xiaonan Wang

    (University of Cambridge)

  • Kenichi Yoshida

    (Kyoto University)

  • Yasuhito Nannya

    (Kyoto University)

  • Hiroo Ueno

    (Kyoto University
    Kyoto University)

  • Ryo Akazawa

    (Kyoto University)

  • Itaru Kato

    (Kyoto University)

  • Takashi Mikami

    (Kyoto University)

  • Kentaro Watanabe

    (The University of Tokyo)

  • Masahiro Sekiguchi

    (The University of Tokyo)

  • Masafumi Seki

    (The University of Tokyo)

  • Shunsuke Kimura

    (The University of Tokyo
    Hiroshima University Graduate School of Biomedical Sciences)

  • Mitsuteru Hiwatari

    (The University of Tokyo
    Teikyo University)

  • Motohiro Kato

    (The University of Tokyo)

  • Shiro Fukuda

    (The University of Tokyo)

  • Kenji Tatsuno

    (The University of Tokyo)

  • Shuichi Tsutsumi

    (The University of Tokyo)

  • Akinori Kanai

    (The University of Tokyo)

  • Toshiya Inaba

    (Hiroshima University)

  • Yusuke Shiozawa

    (Kyoto University)

  • Yuichi Shiraishi

    (National Cancer Center Research Institute)

  • Kenichi Chiba

    (National Cancer Center Research Institute)

  • Hiroko Tanaka

    (Tokyo Medical and Dental University)

  • Rishi S. Kotecha

    (University of Western Australia
    Perth Children’s Hospital
    Curtin University)

  • Mark N. Cruickshank

    (University of Western Australia)

  • Fumihiko Ishikawa

    (RIKEN Center for Integrative Medical Sciences)

  • Tomohiro Morio

    (Tokyo Medical and Dental University)

  • Mariko Eguchi

    (Ehime University Graduate School of Medicine)

  • Takao Deguchi

    (National Center for Child Health and Development
    Mie University)

  • Nobutaka Kiyokawa

    (National Research Institute for Child Health and Development)

  • Yuki Arakawa

    (Saitama Children’s Medical Center)

  • Katsuyoshi Koh

    (Saitama Children’s Medical Center)

  • Yuki Aoki

    (National Cancer Center Japan)

  • Takashi Ishihara

    (Nara Medical University)

  • Daisuke Tomizawa

    (National Center for Child Health and Development)

  • Takako Miyamura

    (Osaka University Graduate School of Medicine)

  • Eiichi Ishii

    (Ehime University Graduate School of Medicine)

  • Shuki Mizutani

    (Tokyo Medical and Dental University)

  • Nicola K. Wilson

    (University of Cambridge)

  • Berthold Göttgens

    (University of Cambridge)

  • Satoru Miyano

    (Tokyo Medical and Dental University)

  • Toshio Kitamura

    (The University of Tokyo)

  • Susumu Goyama

    (The University of Tokyo)

  • Akihiko Yokoyama

    (National Cancer Center)

  • Hiroyuki Aburatani

    (The University of Tokyo)

  • Seishi Ogawa

    (Kyoto University
    Kyoto University
    Karolinska Institute)

  • Junko Takita

    (The University of Tokyo
    Kyoto University)

Abstract

KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.

Suggested Citation

  • Tomoya Isobe & Masatoshi Takagi & Aiko Sato-Otsubo & Akira Nishimura & Genta Nagae & Chika Yamagishi & Moe Tamura & Yosuke Tanaka & Shuhei Asada & Reina Takeda & Akiho Tsuchiya & Xiaonan Wang & Kenich, 2022. "Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32266-4
    DOI: 10.1038/s41467-022-32266-4
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    Cited by:

    1. Derek H. Janssens & Melodie Duran & Dominik J. Otto & Weifang Wu & Yiling Xu & Danielle Kirkey & Charles G. Mullighan & Joanna S. Yi & Soheil Meshinchi & Jay F. Sarthy & Kami Ahmad & Steven Henikoff, 2024. "MLL oncoprotein levels influence leukemia lineage identities," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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