Large granular lymphocytic leukemias (LGLLs), including T-cell LGLL and natural kill (NK)-cell LGLL variants, are rare lymphoproliferative disorders characterized by the chronic proliferation of cytotoxic lymphocytes. Despite recent advancements, challenges remain in distinguishing these entities from one another and from related disorders, such as T-cell prolymphocytic leukemia, adult T-cell leukemia/lymphoma, Sézary syndrome, and aggressive NK-cell leukemia, owing to overlapping clinical and morphologic features. This article aims to review the role of molecular and immunophenotypic markers in guiding diagnosis and prognosis of LGLLs, with brief review of their clinical and morphologic features by synthesizing current advances in molecular pathogenesis, immunophenotypic profiling, and updated World Health Organization (WHO) classification criteria in order to enhance diagnostic precision, improve prognostic assessment, and inform personalized treatment strategies for these challenging disorders.

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A new study conducted by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore has uncovered a key mechanism behind lenalidomide resistance in multiple myeloma (MM), offering new insights into potential strategies for improving treatment outcomes and overcoming drug resistance.

The team, led by Dr Teoh Phaik Ju and Dr Koh Mun Yee, together with Professor Chng Wee Joo and Associate Professor Polly Chen, identified a gene called ADAR1, which encodes an RNA editing enzyme, as a key factor in suppressing the immune response triggered by lenalidomide—an immune-stimulating drug, essential to kill MM cells. The findings were published in the high-impact scientific journal Blood on 13 March 2025.

ADAR1’s role in lenalidomide resistance in MM

MM is a type of cancer that affects plasma cells in the bone marrow. While standard-of-care treatments like lenalidomide, an immunomodulatory drug (IMiD), have improved survival rates for many MM patients, a significant number still experience relapse due to the development of drug resistance.

Lenalidomide works by binding to a protein called cereblon (CRBN), which breaks down several proteins that are essential for MM cell survival and growth. However, many patients eventually stop responding to the drug, leading to disease relapse. While 20 to 30 per cent of the resistance cases have been linked to defects in CRBN and its associated factors, the underlying mechanisms in most resistance cases have remained poorly understood. This study reports new findings demonstrating that ADAR1 abnormalities lead to a suppressed immune system in IMiD-resistant MM cases.

Overcoming drug resistance

ADAR1 inhibits lenalidomide’s activity by editing double-stranded RNA (dsRNA), thus hindering the immune response and reducing the effectiveness of the drug in combating MM growth and proliferation. The researchers discovered that by reducing the levels of ADAR1 and increasing dsRNA accumulation in MM cells, they could increase the sensitivity of the cells to lenalidomide. This would, in turn, lead to the activation of the immune responses and kill the MM cells. The discovery adds a new layer to the understanding of how MM patients may become resistant to IMiD, highlighting the role of dsRNA pathways beyond the previously understood CRBN pathway.

The findings also suggest that targeting ADAR1 and the dsRNA pathway could offer promising strategies to overcome resistance to lenalidomide in MM. As clinical trials continue to explore the potential of new IMiD analogues, such as CRBN-E3 ligase modulators (CELMoDs) and other drugs with similar pharmacological profile, combining these treatments with ADAR1 inhibitors may provide a more effective approach to tackle drug resistance and improve patient outcomes.

With ADAR1 inhibitors currently in preclinical development, this strategy holds great promise for advancing treatment options for MM. In addition, the research team plans to further investigate ADAR1’s role in alternative splicing, a post-transcriptional gene regulatory mechanism, in MM, which could uncover even more opportunities for treatments.