The hepatic niche leads to aggressive natural killer cell leukemia proliferation through the transferrin–transferrin receptor 1 axis

•The liver, a noncanonical hematopoietic organ in adults, serves as a principal niche for ANKL.•Targeting TfR1 with monoclonal antibody PPMX-T003 is a promising strategy for treating ANKL. [Display omitted] Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associa...

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Published in:Blood 2023-07, Vol.142 (4), p.352-364
Main Authors: Kameda, Kazuaki, Yanagiya, Ryo, Miyatake, Yuji, Carreras, Joaquim, Higuchi, Hiroshi, Murayama, Hiromichi, Ishida, Takashi, Ito, Asahi, Iida, Shinsuke, Fukuhara, Noriko, Harigae, Hideo, Fujioka, Yuki, Takahashi, Naoto, Wada, Hidenori, Ishida, Fumihiro, Nakazawa, Hideyuki, Ishihara, Rei, Murakami, Yuki, Tagawa, Hiroyuki, Matsuura, Tadashi, Nakagawa, So, Iwabuchi, Sadahiro, Hashimoto, Shinichi, Imadome, Ken-Ichi, Nakamura, Naoya, Ishizawa, Kenichi, Kanda, Yoshinobu, Ando, Kiyoshi, Kotani, Ai
Format: Article
Language:English
Subjects:
Animals
Cell Proliferation
Epstein-Barr Virus Infections - pathology
Herpesvirus 4, Human
Humans
Leukemia, Large Granular Lymphocytic - pathology
Leukemia, Prolymphocytic, T-Cell
Liver - pathology
Mice
Transferrins
Tumor Microenvironment
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Summary:•The liver, a noncanonical hematopoietic organ in adults, serves as a principal niche for ANKL.•Targeting TfR1 with monoclonal antibody PPMX-T003 is a promising strategy for treating ANKL. [Display omitted] Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established 3 xenograft mice derived from patients with ANKL (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)–transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a noncanonical hematopoietic organ in adults, serves as a principal niche for ANKL and the inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL. Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy characterized by an aggressive clinical course and very poor prognosis. To study its pathophysiology, Kameda et al used patient-derived xenografts to mimic leukemic infiltration into hematopoietic organs, revealing the hepatic sinusoids to be a favored niche. The authors identified the transferrin–transferrin receptor 1 (TfR1) interaction as pivotal to this and demonstrate that an anti-TfR1 antibody has therapeutic potential in this model.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2022018597