The origin of thrombocytopenia caused by an oncogene was discovered

The origin of thrombocytopenia caused by an oncogene was discovered https://i2.wp.com/www.eresviral.com/wp-content/uploads/2018/10/Descubierto-el-origen-de-la-trombocitopenia-causada-por-un-oncogen.jpg?fit=228%2C146&ssl=1

The origin of thrombocytopenia caused by an oncogene was discovered







Scientists at the National Center for Oncological Research (CNIO) (Spain) have discovered that MASTL, a protein whose role in the body is still little known, has an important function of controlling the cytoskeleton, the structure that shapes cells and conditions their mobility and grouping capacity.



Researchers have thus managed to relate the protein to the origin of a heritable type of thrombocytopenia and suggest that the finding could have implications in the fight against cancer metastasis. The finding has been published in the Journal of Clinical Investigation.



To date it was known that MASTL has a role in the regulation of cell division, but not much was known about it. In 2003, a US team identified a group of patients with inherited thrombocytopenia who carried a mutation in the MASTL gene.



Thrombocytopenia is a condition characterized by low levels of platelets in the blood, leading patients to suffer uncontrolled bleeding that can lead to bruising and bleeding. The one of these patients in particular, caused by the mutation in MASTL, is known as autosomal dominant non-syndromic thrombocytopenia, or thrombocytopenia-2.



The CNIO researchers decided to study that specific mutation in the hope that it would lead them to discover more about the functions of the protein. "There was no previous connection that told us how a protein that regulates the division of cells could regulate the number of platelets," says Begoña Hurtado, first author of the article with Marianna Trakala.







The mutation in MASTL produces defects in the morphology of activated platelets, generating abnormal fusiform platelets along with rounded normal platelets. The proteins of the actin and tubulin cytoskeleton are marked in green and red, respectively. (Photo: CNIO)



To find the relationship, they generated a lineage of genetically modified mice that carried the same mutation found in patients with thrombocytopenia-2. Together with the CNIO Proteomics Unit, headed by Javier Muñoz, they discovered that the mutant platelets had a morphology and an altered protein content that gave rise to a defective cytoskeleton.



The cytoskeleton gives stability and shape to the cell, as well as being determinant in its mobility, functioning as a cellular muscle. It also determines the capacity of interaction and grouping of cells. The study has discovered that the mutation in MASTL causes defects in this muscle, which in the case of platelets is essential to form the thrombi that protect from bleeding.



The observations have allowed us to identify the molecular reason why the mutation causes thrombocytopenia-2 in patients, which not only increases knowledge about the actors involved in the origin of the disease, but also allows us to test possible therapies. The researchers were able to avoid the defect caused by the mutation by manipulating other enzymes of the cytoskeleton with chemical inhibitors already available in the clinic.



But the finding that MASTL controls the cytoskeleton may have applications in the investigation of cancer metastasis. "The cytoskeleton is crucial in many cellular functions, but among them are the communication properties between cells or adherence to the environment, that is, those related to migration and invasion," explains Marcos Malumbres, project director.



Metastatic cells undergo a particular process in which they lose adherence to their usual environment, are able to modify their cellular form to escape through the blood capillaries and end up adhering to new tissues initiating the process of metastasis.



The group of Malumbres had already discovered that MASTL could be a therapeutic target whose inhibition could slow the growth of breast tumors: recently, they published in the journal Cell Death & Differentiation the finding that protein levels are increased in some patients , and how its inhibition in experimental mouse models slowed the development of the tumor.



"In the next step of our research we will analyze to what extent the expression of MASTL in tumors can modulate its invasive or metastatic capacity," says Malumbres. This continuation of the work could open new ways to the possible applications of MASTL inhibitors in oncological therapies. (Source: CNIO)

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