The Story of IDH1 and 2

When the astonishingly complex ecosystem that is the human body goes awry, cancers can ensue; but equally when we can tip the scales back to equilibrium, the same cancers can be slowed or even reversed.

     IDH1-2 Mutations at a Glance

  1. IDH1 or IDH2 mutations can appear in any type of cancer, including some blood cancers, some brain tumors such as gliomas, and rarer cancers like cholangiocarcinoma.
  2. In some cancers, IDH1 or IDH2 mutations are very common: Twenty percent of acute myeloid leukemia (AML) patients have a mutation in one of these genes, and so do 75 percent of secondary glioblastoma multiforme (GBM) patients.
  3. Patients with an IDH1 or IDH2 mutation who have gliomas, AML, or intrahepatic cholangiocarcinoma have a better overall prognosis.
  4. Testing for an IDH1/2 mutation requires a cancer cell specimen.
  5. When working properly, IDH1/2 codes for enzymes that help cells consume nutrients and grow. When mutated, instead the genes encode an enzyme that changes how DNA is stored, which can turn on other genes that drive cancer growth.

This Gene is also known as: PICD, IDCD, and IDP

For most of the twentieth century, there were no wolves in Yellowstone. By 1926, the U.S. National Parks Service had the predators exterminated from the park, based in part in fear, but no doubt in large part to the fact that the wolves had a liking for our domestic livestock just as strongly as we did. In their absence, the park, ever the evolving ecosystem, changed. One of the worrisome effects noted by ecologists who studied the area was a decline in the park’s Aspen trees. This was attributed to the apparent influence of the now-increasing elk population: without the wolves to keep the herbivores in check, elk were over-grazing on the young aspen, halting their maturation.

But then, in the 1990s, we brought the wolves back into the park. And the aspens started growing again.

Of course, the relationship between the wolves and the aspen trees is not so simple as plainly stated above. But the relationship is there, nonetheless: the aspens and the elk and the wolves are intractably linked—they are an ecosystem. And to understand human isocitrate dehydrogenase genes (IDH1 and IDH2), it helps to compare the human metabolic system to an ecosystem, to the magnificent chaos of nature writ large.

In the body, IDH1 and IDH2 are genes that encode a metabolic enzyme, IDH, responsible for one of the irreversible steps in the citric acid cycle, one of the major cellular processes that turn the food we eat into usable energy. It is used by all air-breathing organisms to generate energy from carbohydrates, proteins, and fats. Since the enzyme produced by the IDH1/2  genes, isocitrate dehydrogenase (IDH enzyme), is involved in such a critical process, it must be regulated carefully by the body. And, much like the wolves, whose mere presence in an area can change the landscape by affecting the behavior of their prey, the effects of the IDH1/2 genes are far-reaching and difficult to unravel.

What does IDH1/2 do in normal tissue?

In healthy tissues, the isocitrate dehydrogenases encoded by IDH1/2 are involved in one of the early and irreversible reactions in the citric acid cycle, a metabolic Rube Goldberg that is imperative for turning many types of the food that we eat into usable energy for the cell. Because of this, it must be carefully regulated by the cell, to make sure that important steps in the process are not depleted, and to avoid the accumulation of other types of molecules that can drive certain cancerous processes. The enzyme encoded by IDH1/2 normally results in the production of α-ketoglutaric acid (α-KG), another critical component of the aforementioned metabolic cycle; this reaction also involves the production of NADPH, a helper molecule (cofactor) which can be thought of as a kind of cellular currency for making energy. This is important to note, because when the IDH1/2 gene is mutated, these normal cellular mechanism are not only halted, but reversed.

When functioning normally, the product of the IDH enzyme is α-ketoglutaric acid (α-KG), another very important player in cellular metabolism. If the genes are the wolves, these are the prey animals; this is not to imply a predatory relationship within the cell, but that of a regulatory one. The process that creates α-KG also results in the production of another important helper molecule for these reactions, NADPH. Rather broadly, NADPH can be thought of as a kind of critical energetic currency, necessary for the functioning of the metabolic system. This is not unlike the role of vegetation in an ecosystem; much like how the interactions between the wolves and their herbivorous prey can generate more plant matter, the IDH enzyme works to shepherd α-KG, allowing the fields of NADPH to flourish. It follows that much like the removal of the wolves changed the ecosystem of the park, so to does altering the metabolic function of IDH1/2.

Without the wolves in the park, the population of the animals they preyed on grew, meaning more hungry, herbivorous mouths to feed. The vegetation suffered. Willows, holding the river banks in place, were chewed into oblivion, changing the ways the rivers flowed. Young aspen trees were gnawed too early, stunting their stretch to the skies. The ecosystem began to shift course, away from equilibrium, toward something different.

When IDH1/2 is mutated, the product resulting from the enzymatic reaction isn’t the well-regulated production of α-KG but 2-HG (2-hydroxyglutarate dehydrogenase) a wildcard molecule compared to the properly functioning α-KG. When 2-HG accumulates within the cell, it changes the way the DNA is stored in the cell. This can then affect the way genes are activated to make proteins. Specifically, this process can activate (“turn on”) certain genes that cause cancer, known as oncogenes, while also deactivating the genes that suppress tumor formation. And with these changes to the metabolic ecosystem of cells in the body, cancer can get a foothold.

The absence of wolves in the park meant that animals otherwise controlled by their presence begin to grow in number; likewise, with the influx of new mouths to feed, the grasses are consumed instead of being given spaces to grow. Similarly, when IDH1/2 mutations occur and trigger the aforementioned alternate pathway, the NADPH that is normally generated is instead consumed in the process. Just like the grasses in Yellowstone.

IDH1/2 mutations are associated with several different kinds of cancer, but perhaps most closely with stage two and three gliomas, as well as secondary glioblastoma multiforme (GBM). Within these types of brain tumors, mutations in the IDH1 or IDH2 gene are found in upwards of 75% of patients. The mutation is also found in around 20% of patients with acute myeloid leukemia (AML), as well as more sparingly in patients with chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. Because of the mutation’s prevalence in certain cancers, it has become a popular diagnostic and prognostic marker in the identification of low grade gliomas and secondary GBM. Today, we use our ability to detect the mutation on a molecular level to detect cancer within the ecosystem of the body.

Here is what we know about the oncogenic ecosystem it creates.

Because of the pattern with which IDH1/2 mutations occur, scientists believe that changes to these genes might be linked to the processes that determine the fate of the young cells, having specific involvement at a stage where stem cells (immature cells that can mature into different biological roles) are embarking on differentiation; that is, the path towards their specialized, adult form. The fact that IDH1/2 mutations occur at a very early stage of tumor-formation, and are the earliest known mutation in glioma, support the idea that the mutation interferes with the fate of young cells.

It is interesting to note that the presence of IDH1/2 mutations in glioma, AML, and intrahepatic cholangiocarcinoma are associated with better overall prognoses. This clinical finding suggests that the over-production of 2-HG, which stimulates the development of cancer, may actually be self-limiting. Too much of the rogue oncometabolite can actually prove toxic to the cell.

It is not unlike the changes to Yellowstone after the wolves left. These kind of ecosystem shifts, where the artfully stacked food chain begins to sway and topple, are rarely catastrophic in the way, say, a raging forest fire can be. Which is not to imply that both upending a food chain and IDH1/2 mutations alike aren’t capable of causing catastrophic damage, but rather, that the way they go about it is without the violence of untamable flames or a catch-your-breath flood. The slower nature of the change also opens up a tantalizing possibility: reversal.

That these mutations may have a self-limiting aspect to them is of great interest to researchers in the field. Because the IDH1 and IDH2 mutations tend toward producing milder secondary gliomas, it is our hope that by understanding how they enable cancer to gain a foothold in the body we may discover future therapies for cancers associated with this metabolic mutation, as well as related cancers that are known to be more aggressive.

There are two main goals, ideally, in the current search for IDH1/2-specific therapeutics: inhibition and reversal. Researchers have found two compounds that function as selective IDH1/2 inhibitors. The first works against mutated IDH1 genes in glioma, but does not act upon “wild-type” or normal versions of the gene. The second works to selectively inhibit an IDH2 mutant in AML, leading to a reduction in the elevated concentration of 2-HG inside the cells. Not only do these findings earnestly support the search for clinical therapeutics to act on IDH1/2 mutants, but they open the door for the potential for reversal.

Research on therapies to overcome IDH1/2-related disease is moving forward every day. Just as returning the wolves to Yellowstone shifted the park’s ecosystem back to a healthy balance, so too is it the hope of many that correcting the behavior of IDH1/2 mutations may restore balance to a human metabolic ecosystem, stopping or reversing certain cancers.

 

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