The story of viruses and tumors dates back to as early as 1910, an era when the central dogma had not yet been proposed, but scientists at the time believed that if such a pathogen could be identified, preventing or treating tumors would become possible. HPV is an example of this; Professor Harald zur Hausen was awarded the Nobel Prize in 2008 for his discovery of the link between HPV and the causation of cervical cancer. However, in 2005, another type of virus, which usually coexists peacefully with the human body and is infected from birth, the single-stranded DNA circular virus known as Anelloviruses, caught the attention of him and his wife, Professor Ethel-Michele de Villiers. These viruses have a very low load when the immune system is normal, and only replicate explosively in the bone marrow under conditions of immunosuppression (newborns, post-bone marrow/organ transplantation, HIV patients). Although the presence of Anelloviruses was detected in lymphoma and leukemia samples at the time, the association was often overlooked. It wasn’t until 2021 that Dr. Annalisa Astolfi from Italy first reported the detection of a subcategory of Anelloviruses, Torque teno mini virus (TTMV), in acute promyelocytic leukemia cells, and the fusion with the human genome’s retinoic acid receptor α (RARA) opened up research on TTMV::RARA fusion-positive leukemia.

Recently, the team of Wang Kan Kan from Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine published a research paper titled “Infection-related pathway activation and vulnerability to arsenic trioxide in acute promyelocytic leukemia with TTMV::RARA” in the journal Leukemia (https://www.nature.com/articles/s41375-024-02481-7).

This study developed a screening tool based on fusion sequence characteristics to identify TTMV::RARA fusion-positive patients among leukemia patients who had previously undergone RNA sequencing. Using third-generation sequencing technology combined with Sanger-PCR technology, it was confirmed that TTMV integrated into the second intron of RARA, forming a fusion protein that retains a conserved motif in the TTMV part, while also retaining the DNA and ligand-binding domains of RARA. The study collected seven cases with TTMV::RARA fusion sequences or RNA sequencing data, and transcriptome analysis showed that compared to other AMLs, TTMV::RARA-positive cases had a highly similar expression pattern to APL, but also had their own unique expression patterns—activation of infection and immune pathways. Additionally, the study found that the expression patterns of TTMV::RARA-positive cases were highly consistent with those after ATO response. Analysis of the TTMV::RARA fusion protein sequence revealed a conserved cysteine at positions 55-59 on the TTMV side, and previous studies found that arsenic could bind to a binding pocket composed of three cysteines. Structural analysis of the fusion protein revealed that the binding pocket formed by the three cysteines varied in size due to the virus’s own variability. Interestingly, the smaller the pocket, the better the clinical treatment response (the best survived for 11 years, and the worst recurred after 10 months), and the study further used GSVA to calculate the ATO response score, corroborating this finding. Furthermore, the study cloned TTMV::RARA fusion sequences with strong/weak responses to ATO from samples and verified this conclusion in the U937 cell line.

The study also conducted an in-depth discussion on the mechanism of TTMV::RARA fusion occurrence. Based on the findings of this study: 1. RARA has higher expression in TTMV::RARA samples; 2. TTMV viral fragments were detected in the DNA of TTMV::RARA-positive patients, which were not found in other leukemias, indicating that there is a high load of viral DNA in the cells when TTMV::RARA occurs. 3. The insertion site of TTMV viral DNA coincides with the open chromatin region of the second intron of RARA. Therefore, the study proposes a pathogenesis model for TTMV leukemia, where when the body’s immunity declines, the load of TTMV virus in the bone marrow increases dramatically, immune pathways are activated to cope with the infection, bone marrow cells receive differentiation instructions, but when differentiation reaches the promyelocyte stage, which is also the open stage of RARA expression, TTMV inserts into the RARA intron, ultimately forming the TTMV::RARA fusion protein. This study clarifies the molecular characteristics of TTMV::RARA-positive leukemia and proposes ATO as a potential treatment option.

Recruitment of Cases with Abnormal Promyelocyte Increase

If you are a clinician and have patients meeting any of the following conditions:

1. Increased promyelocytes identified by cytomorphology or flow cytometry, with PML::RARA negative results;

2. Diagnosed with myeloid sarcoma;

3. Confirmed to harbor a TTMV fusion.

Please contact us at loujiacheng1986@foxmail.com. We will reach out to you proactively if the case meets our inclusion criteria.

If you are a researcher in a related field and are interested in TTMV leukemia, we also welcome discussions, exchanges, and collaborations.