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New Strategies Against Leukemia
May 7, 2015   
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Patients suffering from chronic myeloid leukemia cannot be fully cured with existing forms of medical treatment. More effective strategies for fighting the disease may emerge as a result of a new insight into signaling pathways in leukemia cells gained by researchers at the Polish Academy of Sciences’ Nencki Institute of Experimental Biology in Warsaw.

The cells of patients suffering from chronic myeloid leukemia, especially at the advanced stage, lack one specific protein: BRCA1. This protein is missing even if the patient has the regular, rather than mutated, gene responsible for BRCA1 production. Scientists from the Nencki Institute have demonstrated that BRCA1 deficiencies in patients in whom the gene is functional are caused by a defective protein synthesis process. The discovery offers a new insight into the mechanism behind the development of leukemia. The research, conducted in collaboration with a group of scientists led by Prof. Tomasz Skorski from the Temple University School of Medicine in Philadelphia, is expected to help improve leukemia diagnostics and help develop better, more efficient forms of treatment for patients.

Chronic myeloid leukemia (CML) is diagnosed in about 25 percent of adult leukemia patients. The disease is caused by the translocation of fragments of chromosomes 9 and 22. This leads to the emergence of a fusion chromosome, known as the Philadelphia chromosome, and a new fusion gene coding a new protein: BCR-ABL1. The presence of BCR-ABL1 results in the activation of signaling pathways that promote and are responsible for the development of chronic myeloid leukemia.

The disease starts with a chronic phase with mild symptoms and then progresses into the highly malignant blast phase associated with the appearance of immature hematopoietic cells (blasts) in the blood. At this stage of the disease, leukemia cells are usually resistant to current therapies.

KatarzynaPiwocka, an associate professor at the Nencki Institute, says, “We are trying to understand the mechanisms responsible for the development of the disease and for the resistance of patients to treatment. We also are looking for strategies to eliminate leukemia cells, including leukemia stem cells, because this is the only way to cure patients with chronic myeloid leukemia.”

Cancer cells accumulate numerous DNA double-strand breaks (DSBs). BRCA1 is one of the crucial proteins involved in DSB repair processes and control of DNA stability. Mutations in the BRCA1 gene are commonly associated with predisposition to breast and ovarian cancer. When BRCA1 is present, cells can faithfully repair DSBs or induce an apoptotic process to eliminate cells with too many breaks. Thus BRCA1 deficiency strongly promotes cancer development. Thanks to previous research conducted by a team led by Piwocka and other research groups, it was known that the BRCA1 level is significantly lower in advanced phases of chronic myeloid leukemia. Previously, these deficiencies were attributed to gene mutations.

Researchers from the Nencki Institute discovered that, in leukemia, another factor is also important and responsible for BRCA1 deficiency. The microenvironment in which cancer cells grow is extremely unfriendly to them. To survive and grow, cancer cells have to activate or change multiple signaling pathways in order to adapt to microenvironmental conditions. One of these protective, survival mechanisms, a signaling pathway known as adaptive stress response, can inhibit synthesis of the BRCA1 protein, the researchers say.

Paulina Podszywałow-Bartnicka, Ph.D., a researcher at the Nencki Institute and the main author of a publication in Cell Cycle journal, says, “Our research demonstrated that BRCA1 synthesis is diminished at an advanced stage of CML. The gene encoding the BRCA1 protein is not mutated, but BRCA1 mRNA, which is necessary for protein production, is aggregated and stored in protein complexes, thus being unavailable for protein synthesis.”

Current diagnostic procedures focus on detecting mutations in the BRCA1 gene. The work by researchers from the Nencki Institute suggests that BRCA1 protein deficiency can occur far more frequently than thought.

The discovery not only increases researchers’ understanding of the biology of leukemia, but most importantly opens the way for new types of anti-leukemia treatment. It is now known that the lack of the BRCA1 protein, which supports cancer, can also be used as a weapon against cancer cells. New forms of treatment based on the concept of synthetic lethality take advantage of the fact that some signaling pathways or genes are inactive or mutated in cancer cells.

Skorski explains, “When a cell has one damaged signaling pathway or gene, it may function properly due to alternative pathways, which usually exist. Only when this alternative pathway is inhibited do cells lose their ability to survive. As we know that one of the DSB repair pathways which depends on BRCA1 is blocked in leukemia cells, we can try to find an alternative, parallel pathway and inhibit it as well. This will lead to the activation of a suicide process—apoptosis, involving a mechanism known as synthetic lethality. This will not be the case in normal healthy cells, because they still have functional BRCA1-dependent signaling. Therapies based on BRCA1 deficiency are currently being investigated in clinical trials.”

Therapeutic regimes routinely used in cases of CML usually do not cure patients. They only make it possible to control the chronic phase of the disease and delay advanced phases. Therapies based on synthetic lethality open new opportunities for the development of personalized therapies that can eliminate leukemia cells, including leukemia stem cells responsible for relapses of the disease.

The studies of signaling pathways in leukemia have been financed with research grants from Poland’s National Science Center, the Polish Ministry of Science and Higher Education, and the National Institutes of Health in the United States.
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