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

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.

SUBMITTER: Isobe T

PROVIDER: S-EPMC9427775 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Isobe Tomoya T Takagi Masatoshi M Sato-Otsubo Aiko A Nishimura Akira A Nagae Genta G Yamagishi Chika C Tamura Moe M Tanaka Yosuke Y Asada Shuhei S Takeda Reina R Tsuchiya Akiho A Wang Xiaonan X Yoshida Kenichi K Nannya Yasuhito Y Ueno Hiroo H Akazawa Ryo R Kato Itaru I Mikami Takashi T Watanabe Kentaro K Sekiguchi Masahiro M Seki Masafumi M Kimura Shunsuke S Hiwatari Mitsuteru M Kato Motohiro M Fukuda Shiro S Tatsuno Kenji K Tsutsumi Shuichi S Kanai Akinori A Inaba Toshiya T Shiozawa Yusuke Y Shiraishi Yuichi Y Chiba Kenichi K Tanaka Hiroko H Kotecha Rishi S RS Cruickshank Mark N MN Ishikawa Fumihiko F Morio Tomohiro T Eguchi Mariko M Deguchi Takao T Kiyokawa Nobutaka N Arakawa Yuki Y Koh Katsuyoshi K Aoki Yuki Y Ishihara Takashi T Tomizawa Daisuke D Miyamura Takako T Ishii Eiichi E Mizutani Shuki S Wilson Nicola K NK Göttgens Berthold B Miyano Satoru S Kitamura Toshio T Goyama Susumu S Yokoyama Akihiko A Aburatani Hiroyuki H Ogawa Seishi S Takita Junko J

Nature communications 20220830 1

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 ...[more]

PMID: 36042201

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Project description:Acute lymphoblastic leukemia (ALL) in infants has a significantly inferior outcome in comparison with older children. Despite initial improvements in survival of infants with ALL since establishment of the first pediatric cooperative group ALL trials, the poor outcome has plateaued in recent years. Historically, infants were treated on risk-adapted childhood ALL protocols. These studies were pivotal in identifying the need for infant-specific protocols, delineating prognostic categories and the requirement for a more unified approach between study groups to overcome limitations in accrual because of low incidence. This subsequently led to the development of collaborative infant-specific studies. Landmark outcomes have included the elimination of cranial radiotherapy following the discovery of intrathecal and high-dose systemic therapy as a superior and effective treatment strategy for central nervous system disease prophylaxis, with improved neurodevelopmental outcome. Universal prospective identification of independent adverse prognostic factors, including presence of a mixed lineage leukemia rearrangement and young age, has established the basis for risk stratification within current trials. The infant-specific trials have defined limits to which conventional chemotherapeutic agents can be intensified to optimize the balance between treatment efficacy and toxicity. Despite variations in therapeutic intensity, there has been no recent improvement in survival due to the equilibrium between relapse and toxicity. Ultimately, to improve the outcome for infants with ALL, key areas still to be addressed include identification and adaptation of novel prognostic markers and innovative therapies, establishing the role of hematopoietic stem cell transplantation in first complete remission, treatment strategies for relapsed/refractory disease and monitoring and timely intervention of late effects in survivors. This would be best achieved through a single unified international trial.

Dataset Information

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

Publications

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

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