In:
Blood Journal, American Society of Hematology, ( 2023-05-05)
Abstract:
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 three ANKL-patient-derived xenograft mice (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 non-canonical hematopoietic organ in adults, serves as a principal niche for ANKL, and that inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.2022018597
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2023
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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