In the advanced stage of chronic myeloid leukemia, the synthesis of the BRCA1 protein itself is disturbed, which at this stage of the disease is its fifth Achilles’ disease, Polish researchers showed. They write about it in the latest issue of the Cell Cycle magazine.
This discovery will help to better predict the development of the disease and develop a new effective therapy to prevent the disease from recurring and to cure it.
So far, the BRCA1 gene has been associated in oncology with a mutation that increases the risk of breast and ovarian cancer. Due to this disorder, Angelina Jolie decided to prophylactically remove both breasts first, and recently also the appendages (ovaries and fallopian tubes).
Research by specialists from the Institute of Experimental Biology M. Nencki of the Polish Academy of Sciences showed that the BRCA1 gene also plays an important role in the advanced form of chronic myeloid leukemia. In this case, however, it is not about its mutation, but about the deficiency of this gene in patients in whom it is also normal.
“This discovery not only explains the mechanism supporting the development of cancer, but also reveals its weakness” – claim prof. Katarzyna Piwocka and Dr. Paulina Podszywałow-Bartnicka. Scientists conducted the research in cooperation with the team of prof. Tomasz Skorski from Temple University School of Medicine in Philadelphia.
Chronic myeloid leukemia is caused by scattered cancerous leukemia cells that circulate through the bloodstream. There are quite a lot of them. In the acute stage of the disease, they can collectively weigh more than 1 kg. Most often it affects people aged 30-40, but it can also occasionally occur in children.
Leukemia cells are caused by a genetic aberration where the ABL gene is transferred from chromosome 9 to chromosome 22, where it binds to the BCR gene. Then the so-called a fusion gene responsible for the production of an abnormal BCR-ABL enzyme (the so-called BCR-ABL tyrosine kinase).
This disorder arises in bone marrow stem cells, i.e. those from which all other cells can arise, in this case produced in the bone marrow. This mutation stimulates the bone marrow to produce an excessive number of immature white blood cells (granulocytes, immune cells), which are more viable and displace those that are normal. They damage the bone marrow and do not adequately protect against infections. When they enter the bloodstream, they also damage internal organs, such as the spleen and kidneys.
The first drug to inhibit the activity of the BCR-ABL mutation, which is crucial for the development of myeloid leukemia, was developed 15 years ago. Several other similar drugs have since been introduced. However, over time, the disease may progress to the so-called blast crisis, when a large number of immature stem cells (blasts) appear in the patient’s blood.
During the blast crisis phase, the leukemia stem cells, as well as the leukemia cells themselves, are resistant to treatment. This may change the discovery of Polish researchers.
Our research has shown that in the advanced stage of chronic myeloid leukemia, the very synthesis of the BRCA1 protein is disturbed. The patient has the correct gene for this protein, but the messenger acid mRNA molecules necessary for its production are folded and wrapped in protein complexes. Hidden in such a way, they cannot participate in the process of protein synthesis – explains the main author of the publication, Dr. Paulina Podszywałow-Bartnicka.
A new treatment could take advantage of the deficiency of the BRCA1 protein. Because what serves cancer cells, in this case can be used against them.
When a cell has damaged one signaling or gene pathway, it can usually continue to function because another, alternative pathway is most likely still active. Only when it is inhibited, the cell loses its ability to function – explains Prof. Skorski
This could be a new treatment strategy for chronic myeloid leukemia. Now that we know that one BRCA1-dependent DNA repair pathway does not work in a leukemia cell, we can look for a complementary pathway and try to turn it off. A leukemia cell would be forced to commit suicide. At the same time, a healthy cell would survive, because it would still have an active BRCA1-dependent repair pathway, the scientist claims.
He adds that such potential BRCA1 deficiency therapies are already being tested. (PAP)