Koutarou Nishimura, Tomoya Isobe, Tsukasa Shigehiro, Masaki Nomura, Weijia Zang, Muran Xiao, Wenjuan Liao, Yui Koike, Akira Nishimura, Aiko Sato‐Otsubo, Hiromi Yamazaki, Hiromi Ito, Shinri Okada, Naomi Matsumoto, Wataru Saika, Yifan Zhang, Yumi Aoyama, Chihiro Hasegawa, Takaya Yamasaki, Yasuo Kubota, Kentaro Ohki, Nobutaka Kiyokawa, Genta Nagae, Kenichi Yoshida, Yasuhito Nannya, Hiroo Ueno, Shiro Fukuda, Kenji Tatsuno, Shuichi Tsutsumi, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, H. Tanaka, Mariko Eguchi, Yuki Arakawa, Katsuyoshi Koh, Takao Deguchi, Daisuke Tomizawa, Takako Miyamura, Eiichi Ishii, Shuki Mizutani, Miyano Satoru, Hiroyuki Aburatani, S. Ogawa, A. Takaori-Kondo, Akihiko Yokoyama, Omar Abdel‐Wahab, Patricia Ernst, Junko Takita, Tomokatsu Ikawa, Masatoshi Takagi, Daichi INOUE
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.