RNA 'sequestration' silences the development of acute myeloid leukemia

An international study, published in the journal Nature Cell Biology, offers a new perspective to better understand the malignant transformation of cells that occurs in this disease

Acute myeloid leukemia (AML) is a cancer very aggressive blood infection that generally occurs in adults and represents one in three diagnosed leukemias. It originates in the bone marrow, where the altered hematopoietic progenitor cells fail to differentiate properly and continue to proliferate uncontrollably.

The genetic complexity of AML makes its treatment difficult, such that despite the important advances that have recently occurred in cancer research, its overall survival After five years it remains at 30%.

Acute myeloid leukemia is a very aggressive blood cancer that usually occurs in adults and originates in the bone marrow.

To increase this low survival rate, a knowledge deeper than what occurs inside an acute myeloid leukemia cell. Thus, new therapeutic targets could be found that would lead to the development of new treatments.

To this end, an international team of researchers led by Bruno Di Stefano from the Stem Cells and Regenerative Medicine Center (STaR) and the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine in the United States, focused on post-transcriptional aspects of gene expression in AML, which is deregulated in cancer cells.

Also participating in the investigation were Florian Grebien, from St. Anna Children's Cancer Research Institute, in Austria and Jose Luis Sardina, from the Josep Carreras Leukemia Research Institute, in Spain. The study is published in the journal Nature Cell Biology.

cellular functioning

La gene expression It includes all the actions that an active gene performs so that its information has an impact on the cell. It usually means making an RNA copy of your information (transcription) and then synthesize proteins from this copy (translation).

Cells have various mechanisms to control gene expression, including post-transcriptional regulation and ensuring their function. When these mechanisms are altered, a oncogenic transformation.

Gene expression includes all the actions that an active gene performs so that its information has an impact on the cell.

The team found that the AML cells had an unusually high number of P-bodies, which are cellular structures related to RNA processing, a key step in gene expression.

Taking a closer look, they discovered that RNA from tumor suppressor genes, those that prevent the oncogenic transformation of the cell, they accumulated there and were not translated, so they could not produce their proteins and, therefore, guide the fate of the cell.

Various proteins involved

Although researchers still do not know all the details of why this 'hijacking' preferentially affects the RNA of tumor suppressor genes, the evidence for it is solid academic approach.

When the researchers forced the P-bodies to dissolve, the cells resumed their anti-cancer programs.

So, when the researchers forced the P-bodies to dissolve, the cells resumed their anti-cancer programs, reconfiguring their genome, restarting healthy gene expression patterns and adopting much more tolerable behavior, either dying or moving towards a non-proliferative state. 

When they delved deeper into the sequestration mechanism in P-bodies, the team found several proteins involved in the formation of these cellular entities, especially DDX6.

In fact, the abolition of this protein, both vitro as in vivo, in animal models of AML and in xenografts of cells from AML patients, destabilized effectively the formation of P-bodies, releasing the RNA trapped therein. In the course of the experiments, no relevant effects were observed in healthy progenitor cells.

An important step in the investigation

José L. Sardina, researcher at the Josep Carreras Institute and main co-author of the study, considers that these results are a important step in acute myeloid leukemia research.

«AML is a heterogeneous disease, therefore, finding a molecular pathway "That it could be an Achilles heel for multiple different subtypes and mutations of this leukemia is very exciting," says Sardina.

“It is a heterogeneous disease, so finding a molecular pathway that could be an Achilles heel for multiple subtypes is very exciting.”

José L. Sardina – Josep Carreras Institute

"Equally important is the fact that the loss of P-bodies had little effect on the production of normal blood cells, demonstrating the potential of therapies aimed at the formation of P-bodies in AML”, he continues.

With these results, researchers not only have a much better understanding of the internal mechanisms that lead to oncogenic transformation in AML, but are also optimistic about the potential for new therapies targeting P-bodies in this leukemia and, perhaps, also in others malignant neoplasms in the future.

Source: SINC Agency

Source: Josep Carreras Leukemia Research Institute