Comprehensive molecular and functional analysis of <i>NUTM1</i> -rearranged leukemia
Abstract
Abstract NUTM1 rearrangement defines a significant subset of B-cell acute lymphoblastic leukemia (B-ALL), particularly in infants lacking KMT2A rearrangements, yet its underlying molecular characteristics remain poorly understood. Here, we establish that NUTM1-rearranged (NUTM1-r) leukemia is a discrete entity characterized by a unique transcriptional and epigenetic landscape, notably featuring global DNA hypomethylation, irrespective of the 5′ fusion partner. Functional interrogation of NUTM1 fusions reveals a dual oncogenic role: they drive commitment toward the B-lymphoid lineage while concurrently conferring potent leukemic stem cell properties. Strikingly, expression of a representative fusion, BRD9-NUTM1, is sufficient to induce serially transplantable B-cell progenitor, prepro–B-like leukemia in vivo, faithfully recapitulating the key molecular and immunophenotypic features of human NUTM1-r B-ALL. Mechanistically, NUTM1 fusions establish an aberrant chromatin state, marked by global enhancement of H3K27 acetylation and the creation of distinctive open chromatin regions that co-opt both B-lineage and stemness-related transcriptional programs, including those involving NF-κB and posterior HoxA genes. In stark contrast to resistant KMT2A-rearranged leukemias, NUTM1-r leukemic cells exhibit a profound sensitivity to chemotherapy. This vulnerability is mechanistically linked to the leukemia's dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, revealing specific vulnerabilities that rationalize their favorable clinical outcomes and suggest opportunities for modified therapeutic strategies.
Article Details
Authors (52)
Koutarou Nishimura
Tomoya Isobe
Tsukasa Shigehiro
1Division of Immunology and Allergy, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
Masaki Nomura
1Department of Cancer Pathology, Graduate School of Medicine, The University of Osaka, Suita, Japan
Weijia Zang
Muran Xiao
Wenjuan Liao
9Department of Pediatrics, Section of Hematology, Oncology and Bone Marrow Transplantation, University of Colorado/Anschutz Medical Campus, Aurora, CO
Yui Koike
Akira Nishimura
Aiko Sato-Otsubo
6Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Hiromi Yamazaki
Hiromi Ito
Shinri Okada
Kobe City Medical Center Hospital, Hyogo, Kobe, Japan
Naomi Matsumoto
Wataru Saika
Yifan Zhang
Yumi Aoyama
Chihiro Hasegawa
Takaya Yamasaki
Yasuo Kubota
4Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Kentaro Ohki
14Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan
Nobutaka Kiyokawa
14Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan
Genta Nagae
15Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
Kenichi Yoshida
Yasuhito Nannya
Hiroo Ueno
16Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Shiro Fukuda
Department of Metabolic Medicine, Graduate School of Medicine, The University of Osaka
Kenji Tatsuno
15Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
Shuichi Tsutsumi
15Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
Yusuke Shiozawa
Yuichi Shiraishi
Kenichi Chiba
Hiroko Tanaka
17Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Mariko Eguchi
Yuki Arakawa
Department of Hematology/Oncology, Saitama Children’s Medical Center
Katsuyoshi Koh
23Japan Children’s Cancer Group ALL Committee, Nagoya, Japan
Takao Deguchi
22Division of Cancer Immunodiagnostics, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
Daisuke Tomizawa
Takako Miyamura
Eiichi Ishii
19Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan
Shuki Mizutani
11Department of Pediatrics and Developmental Biology, Institute of Science Tokyo, Tokyo, Japan
Satoru Miyano
Hiroyuki Aburatani
Seishi Ogawa
Akifumi Takaori-Kondo
Akihiko Yokoyama
26Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan
Omar Abdel-Wahab
Molecular Pharmacology Program, Sloan Kettering Institute
Patricia Ernst
Junko Takita
Tomokatsu Ikawa
1Division of Immunology and Allergy, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
Masatoshi Takagi
Daichi Inoue