Molecular Mechanisms In Cell Nucleus Could Treat Aggressive Leukemia

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Molecular-Mechanisms
ImageSource: yalemedicine.org

Leukemia, or blood cancer, is often categorized as one of the most critical types of cancer, expected to be the reason behind 58,100 deaths in the year of 2018 itself. While the patients suffering from the acute myeloid leukemia tend to not survive more than 5 years at stretch, the treatment approach for this has been very hard to decipher over the years.

A new study (R) conducted by some of the international researchers in the Cincinnati Children’s Hospital Medical Center have recently reported on an overlooked part of the leukemic cell’s internal machinery in which they have found a key to treat the condition, if the findings match up with the requirements as mentioned.

Often times, the only cure of bone marrow transplant for the individuals is not possible to be done for people who are so sick. The group of scientists has now looked into possible machinery inside the leukemic cell known as the spliceosome in which they did find traces of a hyperactive form of protein termed as the IRAK4 which is responsible for a frantic division, thus making the cancer even worse.

With finding the traces of this, the researchers went to target the hyperactive form of the IRAK4 protein in the lab to block their functions in the acute myeloid leukemia cells and then transplanted the same into immunosuppresed mice. This experimental approach found a rapid decrease in the levels of the leukemic cells in the mice.

Daniel Starczynowski, PhD, part of the Cancer and Blood Diseases Institute at Cincinnati Children’s Hospital Medical Center, who is also the senior investigator of this study, stated that it significantly prolonged the survival in the animal models.

Following this finding specifically, Starczynowski along with his other colleagues are taking a look at the existing drugs which do have potential impacts in helping target the hyperactive IRAK4 in the leukemia cells in the body. With the vision and targets cleared, the team of international scientists is working on developing a drug that would specifically target the hyperactive IRAK4 and inhibit it to helps treat not just acute myeloid leukemia but also its precursor disease, myelodysplastic syndromes.

Addressing the progress with this specific study, Starczynowski stated that the added preclinical study and research, the researchers are expected to come up with their still unnamed IRAK4 inhibitor ready for the initial clinical trials in the acute myeloid leukemia patients. Given the urgency for new treatment for this condition, the researchers are working day in and day out to get the process in action.

Starczynowski said that it is very upsetting that the doctors and the scientists can do very little for this condition. Even the new drugs which are being introduced after being fast tracked through the development process only provide the patients with an added time of around six months. The only option for cure is a bone marrow transplant but, for the most part, majority of these patients don’t even qualify for the same. These are the primary reasons why this specific field of medicine is in dire need of an alternative form of treatment that can cure the condition right from the roots.

The findings of this specific study, including the salient use of the IRAK4 drugs would potential end up affecting around 20% of the subset patients suffering from acute myeloid leukemia. They researchers are now looking into the molecular machine in the cell’s nucleus. What this does is help the researchers find the genetic coding miscues which have been found to help fuel the subsets of the AML which is depending on the hyperactive protein IRAK4.

Sequencing in the molecular mechanism – Spliceosome

The Spliceosome is technically not visible to the naked eye but does play a very crucial role in the process. In the genetic approach, it has been found that the spliceosome is the one responsible for editing out the unnecessary snippets of the RNA coding which are known as the introns and exons.

Following that, it again splices the loose snipped ends of the RNA back together which helps ensure that specific proteins involved will do their jobs correctly and without any hindrance.

Alternatively, in the acute myeloid leukemia cells, there are significant mutations in the gene called as the U2AF1 which ends up causing errors through the process of RNA splicing. When the functions of the U2AF1 is normal, the snipped ends of the RNA are joined back together, but when the mutated form of the U2AF1 is the one producing the version of the IRAK4 protein, it produces extra protein sequences known as the IRAK4-L (long).

The combination of this is what ends up disrupting the overall molecular processes involved in the innate immune system and ends up triggering the process of oncogenesis in the myeloid blood cells. All of these disrupted processes is what has been found to be the reason behind the growing aggressiveness of this specific disease altogether.

This specific study did start out when Cincinnati Children’s cancer biologist Kakajan Komurov, who was working on a separate research, found the heightened levels of the IRAK4 proteins in the patient’s cells and then ended up sharing the observation with Starczynowski and then together launched a new project involving further scientists to look into the prospect of correlation between the proteins along with the treatment options for the acute myeloid leukemia.

In order to develop potent and effective treatment options for this, the scientists do need to extend their focus more on the mechanism involved in the process to find a better perspective for the treatment for leukemia.