Unraveling the distinct biology of ATLL: Clinical and genetic divergence from other peripheral T-cell lymphomas

Abstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a distinct entity of peripheral T-cell lymphoma (PTCL) associated with chronic infection by human T-cell lymphotropic virus type 1 (HTLV-1). While ATLL and PTCL-not otherwise specified (PTCL-NOS) share overlapping clinical features, their underlying biology, response to therapy, and patient outcomes are markedly different. To date, there is a lack of comparative studies integrating clinical, sociodemographic, and molecular features are limited, and reliable markers for differentiation. Therefore, our aim was to compare the clinical, sociodemographic, and genetic features of ATLL and PTCL-NOS, and to identify transcriptomic signatures that may distinguish ATLL from other PTCLs, with the goal of improving diagnostic accuracy and therapeutic targeting. Materials and Methods: A retrospective cohort study was performed. Patients were classified according to the diagnosis of ATLL and PTCL-NOS. Descriptive statistics were used to describe the sociodemographics and clinical characteristics. Peripheral blood CD3⁺CD4⁺ T cells were isolated by negative selection and sorted by flow cytometry into CD7⁺CADM1⁻ (putative normal) and CD7⁻CADM1⁺ (leukemic ATLL) subsets. Bulk RNA sequencing was performed, and differential expression analysis was conducted using DESeq2. Key findings were validated at the protein level by Western blot or immunohistochemistry (IHC). Results: A total of 429 patients were included, comprising 220 with ATLL and 209 with PTCL-NOS. The median age at diagnosis was similar between groups (55 years vs. 58 years for ATLL and PTCL-NOS, respectively; p = 0.139). However, sex distribution differed significantly, with a higher proportion of females in the ATLL group (57% vs. 40%; p < 0.001). Most patients in both cohorts presented with advanced-stage disease (stage III–IV: 80% in ATLL vs. 75% in PTCL-NOS; p = 0.343). Functional status varied, a greater proportion of PTCL-NOS patients had ECOG 0–1 (90% vs. 76% in ATLL; p = 0.024). While CHOP-based regimens were common in both groups (ATLL vs. PTCL; 86% vs. 91%, p=0.497), PTCL patients were more likely to have pathologic complete response compared to ATLL (41% vs. 23%, p=0.028). Then RNA-seq analysis was performed on CD4⁺ T-cell subsets isolated from 8 PBMC samples (5 ATLL patients and 3 asymptomatic HTLV-1 carriers). Malignant CD7⁻CADM1⁺ T cells displayed a distinct transcriptional profile compared to CD7⁺CADM1⁻ (putative normal) counterparts. Notably, ZCCHC12 expression was significantly upregulated in leukemic cells (log₂ fold change ≈ 2; p = 0.0306), suggesting a potential role in ATLL pathogenesis. This differential expression was consistently observed across individual samples, highlighting ZCCHC12 as a candidate biomarker for malignant transformation in HTLV-1–associated T-cell populations. Conclusions 1 : There are crucial differences between ATLL and PCTL-NOS in terms of sociographic, clinical profiles, and treatment responses. However, Transcriptomic analysis further revealed distinct gene expression patterns in ATLL, with ZCCHC12 emerging as a potential biomarker of malignant transformation in HTLV-1–associated T-cell lymphomas. We propose this new biomarker as a promising target for tailored diagnosis and therapeutics strategies for patients with ATLL.