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<p>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 <i>KMT2A</i> rearrangement (<i>KMT2A-r</i>) 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 <i>KMT2A-r</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • 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,
  • Junko Takita

摘要

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.