Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma

We previously published about this research in a story titled “Study Provides Greater Understanding of How HTLV-1 Can Lead to Adult T-Cell Leukemia/Lymphoma,” which can be found here. The study was originally published in the Journal of Clinical Investigation. You can view the full text of the study here.

This research team was affiliated with the Imperial College London and Kumamoto University, Japan.

What Happened?

Adult T-cell leukemia/lymphoma (ATL) is a rare type of blood cancer that has a well-known cause: human t cell leukemia/lymphotrophic virus type 1 (HTLV-1). However, the mechanism which allows the virus to trigger the potentially lethal disease is not well understood. In this study, the team of researchers set out to understand the process more fully in hopes of finding a way to prevent the virus from having its way.

Most people that are infected with HTLV-1 will not get ATL; only around five percent of infected people develop the disease, and this usually takes place several decades later. The virus mostly infects CD4+ T-cells and has effects of cell survival, differentiation, and activation; this final aspect, activation appears to be the most important in terms of the ATL disease mechanism. The scientists used T-cell receptor sequencing and single-cell RNA sequencing in order to evaluate how HTLV-1 transforms T-cells into cancer. The team sequenced RNA from over 87,000 individual cells for their research. They compared in ATL patients, virus free donors, and health HTLV-1 carriers.

In most infected people, the virus remains in a latent state, without causing any symptoms or even reproducing; in those that get ATL, HTLV-1 suddenly becomes active and hijacks the activation mechanisms of the T-cells which triggers their transformation into cancer. This activity involves the overproduction of proteins that trigger cell proliferation. This mode of hyperactivation appears to make the affected cells more vulnerable to DNA damage, increasing the change of them transforming into cancer. In addition, affected cells ignore regulatory immune signals.

About Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a rare type of blood cancer that affects T-cells, a form of white blood cell that plays a critical role in the function of the immune system. ATL is triggered by an infection of the HTLV-1 virus. HTLV-1 can be transmitted from mother to child, through contact with infected blood, and through sexual contact. Infection seems to be endemic to certain regions such as Japan, Africa, South America, and the Caribbean. This cancer is placed into four sub-types: smoldering, acute, chronic, and lymphoma-type. The acute and lymphoma-type are considered the most dangerous. Symptoms include lytic bone lesions, visceral involvement, skin lesions, hypercalcemia, and osteolysis. Treatments are limited in effectiveness but may include chemotherapy (including CHOP regimens), brentuximab vedotin, and mogamulizumab. Many patients die within a year of diagnosis. To learn more about adult T-cell leukemia/lymphoma, click here.

Why Does it Matter?

The researchers believe that with this new information on how the virus triggers ATL, they can find a way to intervene and prevent the disease.

“There is therefore a great need to understand how the virus turns our T-cells against us in the progression to cancer. Our work highlights a key mechanism for this change and provides us with new directions to search for ways to interfere with the process, potentially preventing the cancer from developing.” – Masahiro Ono, PhD

Ono believes that there are two possible points of intervention where a therapeutic could prevent ATL:

• Through the use of molecules in order to block the activation signaling
• Or by targeting the proteins that the activated cells release in order to trigger proliferation. Only further research will reveal which mechanism would be most effective.

The team will use the vital data from this study to develop a treatment with a mechanism of action that will halt the overactivation of T-cells, therefore halting the development of ATL in its tracks. As a rare cancer with treatment options of limited effectiveness and relatively poor outcomes, improved therapies are greatly needed to help people living with this rare disease.

“Our study shows that the virus infection induces overactivation of infected T-cells, which may provide the virus opportunities to replicate themselves, while making the infected T-cells vulnerable to cancer-causing mutations. To understand how the virus causes the cancer is a very important step for developing new treatments for the virus-induced leukemia patients.”