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

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, Kenichi Yoshida, Yasuhito Nannya, Hiroo Ueno, Ryo Akazawa, Itaru Kato, Takashi Mikami, Kentaro Watanabe, Masahiro Sekiguchi, Masafumi Seki, Shunsuke Kimura, Mitsuteru Hiwatari, Motohiro Kato, Shiro Fukuda, Kenji Tatsuno, Shuichi Tsutsumi, Akinori Kanai, Toshiya Inaba, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Rishi S. Kotecha, Mark N. Cruickshank, Fumihiko Ishikawa, Tomohiro Morio, Mariko Eguchi, Takao Deguchi, Nobutaka Kiyokawa, Yuki Arakawa, Katsuyoshi Koh, Yuki Aoki, Takashi Ishihara, Daisuke Tomizawa, Takako Miyamura, Eiichi Ishii, Shuki Mizutani, Nicola K. Wilson, Berthold Göttgens, Satoru Miyano, Toshio Kitamura, Susumu Goyama, Akihiko Yokoyama, Hiroyuki Aburatani, Seishi Ogawa and Junko Takita ()
Additional contact information
Tomoya Isobe: The University of Tokyo
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
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
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
Mitsuteru Hiwatari: The University of Tokyo
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
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
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
Junko Takita: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32266-4

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