The "Shanghai Recipe" for Acute Promyelocytic Leukemia: Arsenic Trioxide and All-Trans Retinoic Acid

On September 6, 2020, Professor Zhang Tingdong of the First Affiliated Hospital of Harbin Medical University and Professor Wang Zhenyi of Shanghai Jiao Tong University won the "Life Science Award" of the 2020 Future Science Award for their discovery of the therapeutic effects of arsenic trioxide and all-trans retinoic acid on acute promyelocytic leukemia.

Arsenic trioxide is also known as arsenic, and we often see this poison in costume dramas and martial arts novels. All-trans retinoic acid is a common dermatological drug. How do these two seemingly unrelated drugs become related to the treatment of leukemia?

To answer this question, we first need to know what kind of disease acute promyelocytic leukemia is. Before that, we have to talk about what leukemia is.

1. What is acute promyelocytic leukemia?

1. Leukemia

Leukemia is also known as "blood cancer". Like other cancers, leukemia is caused by excessive proliferation of diseased cells. However, these diseased cells are white blood cells in the blood. According to the degree of differentiation and maturity of leukemia cells and the natural course of the disease, leukemia is divided into two categories: acute and chronic. According to the type of diseased cells, it can be divided into myeloid leukemia and lymphoid leukemia.

2. Acute promyelocytic leukemia

Acute Promyelocytic Leukemia (APL) is a special type of acute myeloid leukemia. As the name suggests, APL is a leukemia caused by the pathology of promyelocytes. The patient's bone marrow examination can reveal abnormal proliferation of promyelocytes. Promyelocytes are the early stage of granulocyte differentiation. If they differentiate normally, they will become eosinophils, neutrophils or basophils, becoming part of the white blood cells in the blood and protecting the body from infection.

Figure 1: Promyelocytes in patients with APL

3. Clinical manifestations of acute promyelocytic leukemia

In addition to the general clinical manifestations of other types of acute leukemia, such as anemia, fever, hepatosplenomegaly, and gingival hyperplasia, APL patients also have abnormal promyelocytes in their bodies, which can reduce platelets in the blood and cause bleeding. In addition, they can also release procoagulant substances, resulting in disseminated intravascular coagulation. Therefore, APL has severe clinical manifestations, and bleeding or embolism is prone to occur during the onset and induction treatment, leading to death.

2. How to treat acute promyelocytic leukemia?

Professor Zhang Tingdong's research on arsenic and Professor Wang Zhenyi's research on all-trans retinoic acid have made the cure rate of APL reach 90%. At present, thanks to the widespread use of these two drugs, APL has become a leukemia that can be cured without hematopoietic stem cell transplantation. How do these two drugs achieve such significant therapeutic effects? The answer lies in human understanding of the molecular mechanism of APL pathogenesis.

1. Pathogenesis of acute promyelocytic leukemia

As we all know, there are 23 pairs of chromosomes in the human body, carrying all the genetic information in the human body. Among them, when chromosomes 15 and 17 are broken and translocated, the PML gene on chromosome 15 will fuse with the gene of retinoic acid receptor α (RARα) on chromosome 17, forming a PML/RARα fusion gene, which makes cells unable to differentiate normally and proliferate abnormally, thereby accumulating a large number of abnormal promyelocytes in the bone marrow, leading to APL. Therefore, this mutation of chromosomes 15 and 17 has also become an important sign for testing APL.

The pathogenesis of APL: Fusion of PML gene and RARα gene

Therefore, in addition to using chemotherapy drugs to kill cancer cells, the method of treating this disease can also be to use drugs to inhibit the PML/RARα fusion protein, allowing the cells to "repent", re-differentiate normally and inhibit their excessive proliferation, thereby improving the condition.

2. Exploring drugs for the treatment of acute promyelocytic leukemia

In the early stages, people used 6-mercaptopurine to treat APL, but the remission rate of this treatment was low. After the treatment was changed to daunorubicin in 1973, the remission rate was improved to a certain extent. However, daunorubicin itself has huge side effects and some patients cannot tolerate it easily.

In the 1970s, Professor Zhang Tingdong discovered that arsenic trioxide in the prescription was particularly effective in treating APL while studying the treatment of leukemia with "Cancer Ling No. 1" based on a folk prescription. In the 1980s, Professor Wang Zhenyi discovered that all-trans retinoic acid was a very effective drug for treating APL while investigating foreign literature and repeating experiments. In 1993, Wang Zhenyi's team and Zhang Tingdong's team conducted collaborative research. They found that the combined use of arsenic trioxide and all-trans retinoic acid therapy can significantly increase the complete remission rate of patients, which is the famous "Shanghai Plan" for treating APL.

(III) Molecular mechanisms of arsenic trioxide and all-trans retinoic acid in the treatment of APL

As research continues to deepen, people have learned that the molecular mechanisms of arsenic trioxide and all-trans retinoic acid in treating APL are similar. They can both bind to the PML/RARα fusion protein that is mistakenly produced in APL patients, thereby rendering the fusion protein ineffective and degrading. In this way, the diseased promyelocytes will stop overproliferating and undergo normal differentiation, thereby reducing their number and improving symptoms.

Chinese scientists, especially Professor Zhang Tingdong and Professor Wang Zhenyi, have made great contributions to curing acute promyelocytic leukemia. To this day, arsenic trioxide and all-trans retinoic acid are still the standard drugs for the treatment of APL worldwide, and this therapy has saved the lives of many patients.

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