Scientists from the Nencki Institute, Warsaw, Poland, showed that BRCA1 deficiencies in case when the gene is functional are caused by defects in the protein synthesis process. Such discovery not only explains the mechanism which supports leukemia development, but also uncovers its weakness. Results of this project performed in collaboration with the group of Prof. Tomasz Skorski from the Temple University School of Medicine in Philadelphia might lead to improvement of diagnostics in leukemia and in the future it might benefit in development of better, more efficient therapies leading to cure of patients.
Chronic Myeliod Leukemia (CML) is diagnosed in about 25% of adult leukemia patients. The disease is caused by the translocation between chromosomes 9 and 22. This leads to generation of the fusion chromosome, known as Philadelphia chromosome, and a new fusion gene coding a new protein: BCR-ABL1 kinase. The presence of BCR-ABL1 kinase results in activation of signaling pathways, which promote and are responsible for development of chronic myeloid leukemia.
The disease starts from a chronic phase with mild symptoms, then progress into the highly malignant blast phase associated with appearance of immature hematopoietic cells (blasts) in the blood. At this stage of the disease leukemia cells are usually resistant to current therapies.
“We are trying to understand mechanisms responsible for development of the disease and resistance to treatment. We also are looking for strategies to eliminate leukemia cells, including leukemia stem cells, because this is the only way to cure CML. We want to find new therapeutic targets for novel, potentially more efficient therapeutic strategies,” says Dr. Katarzyna Piwocka, associate professor at the Nencki Institute.
Cancer cells accumulate numerous DNA double-strand breaks (DSBs). BRCA1 is one of the crucial proteins involved in DSB repair processes and control of the DNA stability. Mutations in BRCA1 gene are commonly associated with predisposition for breast and ovarian cancers. When BRCA1 is present, cells might faithfully repair DSBs or induce apoptotic process to eliminate cells with too many breaks — both would be adverse for the growing cancer. So, the BRCA1 deficiency strongly promotes cancer development. Indeed, due to previous research performed by Dr. Piwocka’s team and other research groups, it was known that BRCA1 level is significantly decreased in advanced phases of CML. Till now, such deficiencies were connected with the gene mutations. Researchers from the Nencki Institute discovered that in leukemia another factor is more important and responsible for BRCA1 deficiency.
Microenvironment, in which cancer cells growth, is very unfriendly for them. To survive and grow, cancer cells have to activate or change multiple signaling pathways, in order to adapt to microenvironmental conditions. One of such protective, prosurvival mechanisms, a signaling pathway known as adaptative stress response — can inhibit synthesis of BRCA1 protein.
“Our data demonstrated that BRCA1 synthesis is diminished in advanced stage of CML. The gene coding for BRCA1 protein is not mutated, however BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes, thus not available for the protein synthesis,” describes Dr. Paulina Podszywałow-Bartnicka, the first author of the publication in the well-recognized Cell Cycle journal.
The current diagnostics procedures concentrate on the detection of mutations in BRCA1 gene. The work presented by researchers from the Nencki Institute suggests that the BRCA1 protein deficiency can apply more frequently than we supposed.
This discovery not only increases our knowledge about the biology of leukemia, but most importantly opens way for novel anti-leukemia therapies. We know today, that the BRCA1 deficiency, which supports cancer, can be also used as a weapon against cancer cells. Novel anti-tumor therapies based on the concept of synthetic lethality take advantage from the fact that some signaling pathways or genes are inactivated or mutated in cancer cells.
“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways, which usually exist. Only when this alternative pathway is inhibited, cell lose the ability to survive,” explains Prof. Tomasz Skorski, and adds: “As we know that one of the DSB repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well. This will lead to activation of suicide process — apoptosis by mechanism known as synthetic lethality. This will be not the case in normal healthy cells, because they still have functional BRCA1-dependent signaling. Therapies based on BRCA1 deficiency are currently investigated in clinical trials.”
Therapeutic regimes routinely used in CML usually do not cure patients. They allow to control the chronic phase of the disease and delay advanced phases, however they do not protect from resistance. Therapies based on the synthetic lethality open new possibilities to develop novel, personalized therapies, which can eliminate leukemia cells, including the leukemia stem cells, which are responsible for disease relapse and malignant progression.