Inhibiting heme production could slow down or even cure AML, researchers suggest.
In 2014 alone, leukemia affected around 387,728 people people in the United States, according to data from the Surveillance, Epidemiology and End Results Program of the National Cancer Institute (NCI).
Acute myeloid leukemia (AML) is a particularly aggressive form of cancer that affects the blood and bone marrow. According to the NCI, in 2017, there will be approximately 21,380 cases of AML, and around 10,590 deaths will be caused by it among the adult population.
St. Jude's Children Research Hospital in Memphis, TN, reports that approximately 500 children are diagnosed with AML each year, and while that might not seem like a large number, AML is also the most common type of second cancer developed by children.
New research led by Dr. John Schuetz, from St. Jude's Children Research Hospital, has now made a breakthrough in identifying what allows AML to survive in the system.
Heme production sustains AML
The scientists found that heme, a chemical structure found in hemoglobin, is key to understanding why AML persists in the system, and that it may also provide a new path to treating this type of leukemia. The findings have recently been published in JCI Insight.
In addition to being involved in hemoglobin's oxygen-transporting role, heme is also involved in electron transfer, which supports cellular respiration, allowing oxygen to be transformed into carbon dioxide and release energy.
The researchers found that heme production sustains the progression of AML, and that by suppressing its synthesis, cancerous cells can be neutralized.
Dr. Schuetz emphasizes the importance of this discovery, noting that no clear link between heme production and leukemia had previously been identified. He says, "Absolutely nothing was known about the role of heme biosynthesis before our work."
The first step in identifying the key role played by heme in leukemia was to do a thorough search using the database of St. Jude's, with the aim of identifying additional genes activated by a particularly aggressive form of AML.
This virulent AML is "powered" by the MYCN oncogene, which has a key role in cell division and cell self-destruction. As a result of the database search, the scientists revealed that another gene, called UROD - which stimulates the production of heme - is overactive in the case of leukemia patients.
According to Dr. Schuetz, another crucial finding in this context was that leukemias driven by the MYCN gene, which showed particularly exacerbated UROD activity, were especially aggressive and likelier to lead to patient death.
Laboratory tests showed that cells with an anomalous MYCN activity absorbed larger quantities of oxygen, thus depending on heme production to self-renew. That being the case, the researchers also found that when heme production was prevented, so was self-renewal, which effectively led to slowing down leukemia progression.
Potential pathways for treatment
Self-renewal could also be prevented by inhibiting a protein that removes a heme component from the cells. This caused a buildup of molecules that are toxic to cancerous cells, leading to their destruction. Also significant is that blocking this protein in healthy cells had no negative impact.
In a preclinical study, the researchers looked at the effect that removing the MYCN gene would have. They note that, in this approach, leukemia progression was slowed down, and the likelihood of survival increased.
Also, it was found that leukemia could be cured in preclinical models by inhibiting the protein and disrupting heme production. Dr. Schuetz explains that their study suggests two new approaches to treating AML.
"One would be to target UROD, which would reduce heme biosynthesis. [...] The other strategy would be to use drugs to inhibit the relief-valve protein and at the same time administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway."
Dr. John Schuetz
These findings have even farther-reaching implications, according to the scientists. They suggest that similar treatment strategies could be applied to other types of cancer reliant on heme overproduction, such as a type of medulloblastoma.
In the future, Dr. Schuetz and his colleagues aim to gain an even more detailed understanding of the role of heme in AML, investigating whether or not other cellular roles of heme might be significant in the development of leukemia.
The researchers would also like to test treatments that suppress UROD activity, in order to learn whether they could inhibit AML.