The role of an enzyme in the development of lymphomas revealed

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The role of an enzyme in the development of lymphomas revealed

Work carried out in Quebec gives hope for the creation of a less toxic treatment against lymphomas and certain leukaemias.

3D illustration of a Burkitt lymphoma cell.

The role of an enzyme involved in the malignant transformation of lymphomas is better understood thanks to the work by Marion Lacroix, doctoral student in the laboratory of Professor Tarik Möröy of the Montreal Clinical Research Institute (IRCM).

The researcher and her team discovered that the DDX3X gene, and the specific enzyme it encodes, are necessary for the development and progression of Burkitt's lymphoma.

Their experiments show that a strain of mice with spontaneous lymphoma no longer develop tumors or recurrences when DDX3X is eliminated by genetic engineering.

Flags

  • There are over 80 types of lymphoma.
  • Lymphomas are cancers that originate from a malfunction in the production of lymphocytes, white blood cells that circulate in the blood, bone marrow and lymph nodes.
  • Burkitt's lymphoma accounts for 30% to 40 % of childhood lymphomas. It occurs in children between the ages of 5 and 10 and in adults between the ages of 30 and 50. It strikes men more than women.
  • The most common symptoms of Burkitt's lymphoma are swollen lymph nodes and abdominal swelling.
  • Very aggressive, this cancer usually develops in organs such as the spleen, in glandular tissues such as the thyroid or the tonsils, or in the spinal cord. It can also cause large masses of tissue that disfigure patients.
  • Genetic predispositions and certain environmental factors such as pollution increase the risk of developing this type of lymphoma.
  • It can also be associated with a viral infection such as the human immunodeficiency virus (HIV) and the Epstein-Barr virus (EBV). Moreover, it is endemic on the African continent because of its association with this virus.

B lymphocytes, involved in Burkitt's lymphoma, are actors essentials of the immune system. These white blood cells are responsible for the production of antibodies.

3D reconstruction of a B lymphocyte.

We need it in our battle against viruses or infections, explains Tarik Möröy.

However, it happens that chromosomal rearrangements in the cells push them to develop without control.

“A lymphoma, like Burkitt's, is a cancer of blood cells that go off the rails and multiply to form cell masses. »

— Tarik Möröy, Director of the Hematopoiesis and Cancer Research Unit at the IRCM

These lymphomas are caused by translocations [rearrangements] chromosomes of MYC, a gene involved in cell division. […] It is this translocation that creates a hyperactivation that leads the cells to divide in a totally uncontrolled way, adds Marion Lacroix.

This type of cancer is usually treated by surgical removal of the tumors combined with chemotherapy.

Initial lymphomas usually show good remission rates.

If the disease is treated early enough, the survival rate can reach 90% after chemotherapy treatment. If it is treated a little later, it still reaches 80%. These are good cure rates, notes Ms. Lacroix.

It is the risks of cancer recurrence that are the most worrying, since the chemo treatment is very toxic, because it uses high doses of very powerful drug agents that have the potential to kill all cells, whether they are cancerous or normal.

Aggressive chemotherapy can fix the lymphoma problem, but cause other cancers later in life. This is particularly a problem in the case of young people, Prof. Möröy points out.

“If lymphomas come back, they become very, very difficult to treat. »

— Tarik Möröy, Director of the Hematopoiesis and Cancer Research Unit at the IRCM

Pr Möröy and his student now hope that their discovery may lead to a combination of treatments.

“We hope to use DDX3X as a therapeutic target. This enzyme is active, which means that it can be inhibited. »

— Tarik Möröy, Director of the Hematopoiesis and Cancer Research Unit at the IRCM

It must be said that the three-dimensional structure of the DDX3X enzyme has several folds and pockets and is an ideal target for small molecules to bind to it and inhibit its activity.

Details of this work are published in the journal Cancer Research.

The professor explains that another team in his laboratory treated human Burkitt's lymphoma cells with DDX3X inhibitor molecules which they transplanted into mice in order to see in vivo their effect on the development of human lymphoma. If this other study is still not published, Pr Möröy is very encouraged by the results obtained.

“We are still a long way from treatments for patients, but we are getting closer step by step. »

— Tarik Möröy, Director of the Hematopoiesis and Cancer Research Unit at the IRCM

The researcher believes that research on inhibitory molecules could advance rapidly in clinical trials if they do not prove to be too toxic in preliminary tests.

The objective would be to create a treatment combining DDX3X inhibitor molecules with chemotherapy less powerful.

“We want to show that by combining them with chemo, inhibitory molecules can be more effective and reduce the harmful effects of a dose of chemo. »

— Tarik Möröy, Director of the Hematopoiesis and Cancer Research Unit at the IRCM

Pr Möröy now wants his laboratory to test combinations of inhibitors of this enzyme with conventional chemotherapeutic drugs, with the aim of reducing their dosage and thus reducing their toxicity and the significant side effects.

In addition , Prof. Möröy asserts that a DDX3X inhibitor therapy could also be effective against certain types of leukemias which present the same vulnerability of overexpression of DDX3X and MYC.

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