Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement

Takashi Mikami, Itaru Kato (), Akira Nishimura, Minenori Eguchi-Ishimae, Tatsuya Kamitori, Keiji Tasaka, Hirohito Kubota, Tomoya Isobe, Yoshinori Uchihara, Yui Namikawa, Satoru Hamada, Shinichi Tsujimoto, Shotaro Inoue, Takayuki Hamabata, Kazushi Izawa, Takako Miyamura, Daisuke Tomizawa, Toshihiko Imamura, Hidemi Toyoda, Mariko Eguchi, Hiroaki Goto, Seishi Ogawa, Masatoshi Takagi, James Badger Wing and Junko Takita ()
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Takashi Mikami: Kyoto University
Itaru Kato: Kyoto University
Akira Nishimura: Institute of Science Tokyo
Minenori Eguchi-Ishimae: Ehime University Graduate School of Medicine
Tatsuya Kamitori: Kyoto University
Keiji Tasaka: Kurashiki Central Hospital
Hirohito Kubota: Kyoto University
Tomoya Isobe: University of Cambridge
Yoshinori Uchihara: Kyoto University
Yui Namikawa: Institute of Science Tokyo
Satoru Hamada: University of the Ryukyus
Shinichi Tsujimoto: Yokohama City University Graduate School of Medicine
Shotaro Inoue: Kobe University Graduate School of Medicine
Takayuki Hamabata: Kurashiki Central Hospital
Kazushi Izawa: Kyoto University
Takako Miyamura: the University of Osaka Graduate School of Medicine
Daisuke Tomizawa: National Center for Child Health and Development
Toshihiko Imamura: Kyoto Prefectural University of Medicine
Hidemi Toyoda: Mie University Graduate School of Medicine
Mariko Eguchi: Ehime University Graduate School of Medicine
Hiroaki Goto: Kanagawa Children’s Medical Center
Seishi Ogawa: Kyoto University
Masatoshi Takagi: Institute of Science Tokyo
James Badger Wing: Osaka University
Junko Takita: Kyoto University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Lineage switching (LS) is the conversion of cancer cell lineage during the course of a disease. LS in leukemia cell lineage facilitates cancer cells escaping targeting strategy like CD19 targeted immunotherapy. However, the genetic and biological mechanisms underlying immune evasion by LS leukemia cells are not well understood. Here, we conduct a multi-omics analysis of patient samples and find that lineage-switched acute myeloid leukemia (LS AML) cells with KMT2A rearrangement (KMT2A-r) possess monocytic myeloid derived suppressor cell (M-MDSC)-like characteristics. Single-cell mass cytometry analysis reveals an increase in the M-MDSC like LS AML as compared to those of lineage-consistent KMT2A-r AML, and single-cell transcriptomics identify distinct expression patterns of immunoregulatory genes within this population. Furthermore, in vitro assays confirm the immunosuppressive capacity of LS AML cells against T cells, which is analogous to that of MDSCs. These data provide insight into the immunological aspects of the complex pathogenesis of LS AML, as well as development of future treatments.

Date: 2025
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DOI: 10.1038/s41467-025-63271-y

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