Acute myeloid leukemia: genetics, prognosis and treatments

Published on January 31, 2016   38 min

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Other Talks in the Series: Cancer Genetics

Welcome, today's seminar is on the genetics of acute myeloid leukemia. I'm Stephen Nimer. I'm a physician scientist and I'm the director of the Sylvester Comprehensive Cancer Center at the University of Miami's Miller School of Medicine.
Today I'd like to introduce the disease to you, AML, Acute Myeloid Leukemia, talk a bit about the way we classify this disease, talk about our insights into the pathogenesis or what triggers the growth of these abnormal cells and then lastly, spend some time talking about how we treat this disease both the conventional treatments and some of the latest research that's providing potential new therapies for this disease.
So when you think about cancer in general, you think about a cell that grows abnormally and in acute myeloid leukemia, there are two main attributes. First, the cells don't go through the normal differentiation process. And second of all, the cells proliferate and self-renew abnormally. So really the task is to explain what those two properties of AML mean. There are three types of cells in the peripheral blood. There are white blood cells, red blood cells, and platelets. The white blood cells help us with our immune system and to fight infection, the red blood cells carry oxygen, and platelets prevent us from bleeding. These cells are functional. They are what we call mature cells. And they're all derived from immature cells in the bone marrow. And so the normal immature cells in the bone marrow have no function, but as they mature, they acquire functional characteristics and differentiate into these three different types of cells. So what happens in AML is that these early cells, which we refer to as "blast cells" do not differentiate into normal cells and so they never acquire the normal functional attributes. Instead they accumulate in the bone marrow, which is where they normally live and they spill out into the blood stream. But what happens is they crowd out the normal cells and so over time, a patient will present with leukemia because they have too many of these cells in their blood but really they present because they have too few normal cells. So if you have too few white blood cells then you develop an infection. And if you have too few red blood cells, which carry oxygen, you can't breathe properly and you get short of breath and you get fatigue. And if you don't have enough platelets, you develop bleeding problems, in particular, bleeding into your skin or into the gums of your mouth. And so the way patients present is often with a fever, with fatigue, with bleeding problems, and that leads to the diagnosis of acute myelogenous leukemia or AML.
This is a very interesting drawing from the time of the plague and it shows Italian physicians going out to take care of patients with the plague. This character has a beak. The beak is filled with flowers because they thought if you smelled flowers, you wouldn't get the plague. There's a long black coat, also to prevent the plague. There are gloves, stick, a hat and all of these were thought to be appropriate ways to prevent physicians from getting the plague as they're out in the community taking care of people. Now, the seminal investigation in the plague was the discovery that it was caused by a bacteria called Yersinia pestis, and although the plague in the 15th century and other centuries killed millions or tens of millions of people, if any of us caught the plague today, we would simply take an antibiotic and we would be fine. So, the key to treating the plague was to understand the cause of the plague. And similarly, the key to treating cancer is to understand what causes cancer.
Acute myeloid leukemia is a disease of the elderly. So if you look decade-by-decade, you can see that the incidence goes up and really the average patient with AML is diagnosed around age 65 or 70, and what this reflects is the accumulation of some mutations that can occur in infancy. There are infant leukemias but more commonly, leukemia occurs in an adult. We now understand that there are some mutations that occur within these, either the blast cells that I mentioned, or the hematopoietic stem cells. Hematopoietic stem cells being again, normal cells that can go on and form all the different elements of the blood and that as we age, sometimes we acquire mutations and even in the absence of specific mutations, all at once, patients can present with leukemia and have a series of mutations. The analogy to the plague on the last slide relates to our knowledge of these mutations because we now, through conventional cytogenetics, through whole genome sequencing, and through a variety of techniques, we can now understand the complement of mutations that drive the leukemia in different patients. One of the questions I'm always asked as a physician is why did I get this disease? There are families which have a strong family history of AML or leukemia and in general, the affected family members have a mutation in a gene that's important in blood formation. Two of the most common are in a gene called RUNX1, R-U-N-X 1, or a gene called CEBP alpha, and we now understand that if you are born into one of these families, that decades later, you may present with leukemia, so that the initial mutation is not enough to give you the disease, but subsequent mutations are. And so, other than these families, we really don't know what causes acute leukemia. The only example really of an inciting event occurred with the atomic bombs during World War II in Japan, and so we know that some of the people who lived through that bombing that were exposed to significant radiation can develop either chronic leukemia or acute leukemia. And so we do know that being exposed to radiation can do that. The other example which we do see is patients who develop acute myelogenous leukemia as a result of the chemotherapy that they received for another cancer. And so in that situation, there are some specific chromosome abnormalities that are triggered by the chemotherapy and by the radiation that can lead to a secondary leukemia and there are really two classes of drugs that can trigger leukemia. One affects an enzyme that's involved in DNA repair called topoisomerase inhibitors. And the other are the alkylating agents and alkylating agents kill cancer by damaging the DNA. And so what happens when patients are exposed to these chemotherapy drugs is that there's inadvertent damage to the DNA in the bone marrow cells and this leads over time to the development of leukemia.

Acute myeloid leukemia: genetics, prognosis and treatments

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