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Using RNA sequencing analysis, researchers at University of Tsukuba have classified T-follicular helper lymphoma, a type of blood cancer, according to genomic abnormalities and the tumor microenvironment. Each classification has different clinical characteristics and outcomes. These findings may contribute to treatment optimization.

Tsukuba, Japan—T-follicular helper (TFH) lymphoma is a blood cancer subgroup that continues to demonstrate a generally poor prognosis, with no standard treatment established to date. Although specific genetic mutations are frequently observed in this disease, the association between genomic abnormalities, and clinical features and prognosis remains unclear.

In this study, 94 cases of TFH lymphoma and 35 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), a related disease, were analyzed using whole-exome sequencing. From 35 frequently occurring genetic abnormalities, three molecular classifications (C1, C2, and C3) were identified. C1 and C3 shared mutations in epigenetic regulators recognized in TFH lymphoma, with RHOA G17V mutations commonly observed. However, C3, characterized by chromosome 5 amplification and IDH2 mutations, was associated with a worse prognosis than C1. C2 mainly consisted of peripheral T lymphomas, not otherwise specified, with chromosomal aneuploidy and TP53/CDKN2A abnormalities. It also included some TFH lymphomas and had a poor prognosis. Additionally, RNA sequencing analysis classified the tumor microenvironment into three types: TME1, TME2, and TME3. Of these, TME2, marked by increased M2 macrophage fraction, was linked to poor outcomes and overlapped with C2 in many cases. In conclusion, this study clarified the molecular characteristics of TFH lymphoma, particularly in cases showing a poor prognosis.

These research findings are potentially useful for optimizing TFH lymphoma treatment and may serve as a basis for the development of new treatment strategies.

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This work was supported by Grants-in-Aid for Scientific Research (KAKENHI: JP19K23879 and JP21K16262 [Y. Suehara], JP23K15317 [SS], JP20J20851 [YA], JP23K15316 [KH], JP23K15293 [K. Makishima], JP21K16261 [T. Sakamoto], and JP21H02945 [MS-Y)] from the Ministry of Education, Culture, Sports, and Science of Japan; AMED under grant numbers JP23tk0124002, JP24ck0106908, JP23ck0106797, and the Moonshot Research and Development Program (JP22zf0127009) (to MS-Y); Kobayashi Foundation for Cancer Research, Kobayashi Foundation, Chemo-Sero Therapeutic Research Institute, Takeda Science Foundation, and Uehara Memorial Foundation (to MS-Y). Gilead's Research Scholars Program and a grant from The Leukemia & Lymphoma Society (Grant ID: 3442-25) provided support (to MF).

Original Paper

Title of original paper:

Discrete genetic subtypes and tumor microenvironment signatures correlate with peripheral T-cell lymphoma outcomes

Journal:

Leukemia

DOI:

10.1038/s41375-025-02563-0

Correspondence

Professor SAKATA-YANAGIMOTO Mamiko
Assistant Professor SUEHARA Yasuhito
Institute of Medicine, University of Tsukuba

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Institute of Medicine