New research led by Dr. Javeed Iqbal, a professor in UNMC’s Department of Pathology, Microbiology and Immunology, and colleagues is helping clarify how loss of the TET2 gene contributes to the development of angioimmunoblastic T-cell lymphoma (AITL), an aggressive form of peripheral T-cell lymphoma (PTCL) with limited treatment options.
Published in the Journal of Experimental Medicine, the study shows that loss of TET2 can alter the biology of CD4-positive T cells, promoting abnormal proliferation and transformation into lymphoma. Previous genomic studies have identified TET2 mutations in approximately 80% of patients with AITL, highlighting the potential importance of this pathway in the disease (PMID: 42047684). TET2 is an enzyme involved in regulating gene activity through changes in DNA methylation.
To better understand its role in lymphoma development, Iqbal’s team generated mice in which the Tet2 gene was selectively deleted in CD4-positive T cells. These mice developed an aggressive T-cell lymphoma with a T-follicular helper (TFH)-like immunophenotype, providing a model for investigating how TET2 deficiency may drive disease.
Dr. Iqbal said researchers found that TET2 loss enhanced ICOS-mediated PI3K signaling, a pathway involved in T-cell growth and survival. Increased activity of this pathway contributed to abnormal T-cell proliferation. Studies of human TET2-deficient CD4-positive T cells showed similar changes, including increased proliferation, expansion of specific T-cell clones, and reduced markers of cellular exhaustion.
The study also points to potential therapeutic strategies, he said. In mouse models, the epigenetic drug 5-azacytidine and the PI3K inhibitor duvelisib slowed lymphoma progression, either alone or in combination. These findings provide a biological rationale for investigating approaches that target both epigenetic dysregulation and PI3K signaling in TET2-deficient T-cell lymphoma (PMID: 42047684).
Recent clinical data on duvelisib further highlights the potential relevance of these findings, Dr. Iqbal said. Researchers at Memorial Sloan Kettering Cancer Center evaluated the PI3K inhibitor in the phase II PRIMO trial, which included 123 patients with relapsed or refractory PTCL. The study reported an overall response rate of 48%, with particularly encouraging activity in patients with AITL, where the objective response rate was 62.2% (PMID: 42018969).
“Together, these findings highlight the potential importance of the TET2–PI3K signaling axis in AITL and other T-cell lymphomas,” Iqbal said. “They also suggest that combining approaches aimed at correcting epigenetic abnormalities with targeted inhibition of PI3K signaling may represent a promising area for future investigation.”