Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement
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.
Authors
- Toshihiko Imamura (ORCID: https://orcid.org/0000-0002-5727-4470)
- Akira Nishimura (ORCID: https://orcid.org/0000-0002-9127-807X)
- Masatoshi Takagi (ORCID: https://orcid.org/0000-0002-7580-9184)
- Minenori Eguchi‐Ishimae (ORCID: https://orcid.org/0000-0002-6998-279X)
- Takayuki Hamabata (ORCID: https://orcid.org/0000-0002-1601-0487)
- Daisuke Tomizawa (ORCID: https://orcid.org/0000-0003-1520-7007)
- Takashi Mikami (ORCID: https://orcid.org/0000-0003-1846-4500)
- Keiji Tasaka (ORCID: https://orcid.org/0000-0002-2708-3876)
- Hiroaki Goto (ORCID: https://orcid.org/0000-0001-6737-1509)
- Takako Miyamura (ORCID: https://orcid.org/0000-0002-3226-556X)
- Mariko Eguchi (ORCID: https://orcid.org/0000-0001-8727-1732)
- Shin‐ichi Tsujimoto (ORCID: https://orcid.org/0000-0001-5738-4138)
- Yoshinori Uchihara (ORCID: https://orcid.org/0000-0001-6006-4362)
- James B. Wing (ORCID: https://orcid.org/0000-0002-3462-1003)
- Itaru Kato (ORCID: https://orcid.org/0000-0002-2932-4960)
- Tomoya Isobe (ORCID: https://orcid.org/0000-0002-3487-3307)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Kazushi Izawa (ORCID: https://orcid.org/0000-0003-1080-0936)
- Tatsuya Kamitori (ORCID: https://orcid.org/0009-0003-0472-4663)
- Junko Takita (ORCID: https://orcid.org/0000-0002-2452-6520)
- Satoru Hamada (ORCID: https://orcid.org/0000-0001-5504-0366)
- Hidemi Toyoda (ORCID: https://orcid.org/0000-0002-4727-6050)
- Yui Namikawa
- Hirohito Kubota (ORCID: https://orcid.org/0000-0002-6935-5120)
- Shotaro Inoue
Institutions
- Mie University (JP)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Kyoto University (JP)
- University of Cambridge (GB)
- Karolinska Institutet (SE)
- Osaka City University (JP)
- University of the Ryukyus (JP)
- Osaka University of Human Sciences (JP)
- Kyoto Prefectural University of Medicine (JP)
- Kurashiki Central Hospital (JP)
- Kanagawa Children's Medical Center (JP)
- Kobe Children's Hospital (JP)
- National Center For Child Health and Development (JP)
- Ehime University (JP)
- Osaka International University (JP)
- Kobe University (JP)
- Yokohama City University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1038/s41467-025-63271-y
- Citations
- 2
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- Japan Agency for Medical Research and Development
- Kyoto University
- Takeda Medical Research Foundation
- Princess Takamatsu Cancer Research Fund
- Japan Society for the Promotion of Science