Chronic Myelomyocytic Leukemia: Recent Insights in Pathogenesis

peaker: Eric Solary
Department: Department of Hematology
Subject: Chronic Myelomyocytic Leukemia: Recent Insights in Pathogenesis
Location:
Erasmus Medical Center
Date: 19 December 2016
Author: Romano van Genderen

Professor Eric Solary, director of the prestigious Gustave Roussy Institute of Oncology, had his talk on chronic myelomyocytic leukemia (CMML). This disease has both traits of myeloproliferative neoplasms and myelodysplastic syndrome. So you both have too many excessive cell production and cells not differentiating properly into their final state. So you have too many undifferentiated cells. Currently, you firstly check if the patient has monocytosis for over three months. Next, diagnosis is done using a cross-out method by checking for 3 common diseases and if the patient does not have one of those 3 you call it CMML.

Firstly, he showed that there are 3 distinct kinds of monocytes, namely classical, intermediate and non-classical monocytes. When a patient has CMML, more than 94% of the monocytes are of the classical subtype, while other diseases like CMML have a overproduction (dysplasia) of all three subtypes. These three subtypes can be distinguished from each other using FACS. Using this technology it has been shown that using demethylating agents on CMML patients makes the original distribution return.

facs 
Fig 1. Left: Normal healthy patient, having a normal distribution. Right: Diseased patient with mostly classical monocytes (Green)

Secondly he analyzed the genetic causes of CMML. Firstly, he found that juvenile MML is often caused by over-activation of the RAS, making the blood stem cells more likely to differentiate to common myeloid progenitor cells. But in CMML there are many genes related to the disease. But these genes have in common that they regulate epigenetic markers, splicing and signaling molecules.

Next he investigated the clonal architecture, so which cell types are present where and when. He showed that the mutations that cause CMML give the cells a selective advantage, since the mutated stem cells do quickly outpopulate the non-mutated cells. It was also seen that the order in which mutations occur is most often first a change in epigenetic regulation, then splicing and finally signaling. This is an example of the multi-step model of cancer. Also, a mutation in the TET2 gene makes the cell more likely to become a myeloblast, the cell right before the monocyte. Also mutations that cause the cell to be more sensitive to signals that promote differentiation.

Treatment of this disease is very hard and prognosis is not always clear. One of the ways to treat the disease is hypomethylating agents, which remove methyl groups from DNA. But only 40% responds to this treatment. This medicine does not remove the mutations or lower the risks of new mutations occurring, but it stops the monocytes from differentiating to the classical subtype. The difference between responders and non-responders is the baseline DNA methylation.

Next, he showed that epigenetic regulation plays a large role in this disease. They found out that the gene TRIM33 is downregulated by an epigenic cause. A large clue was recently found, namely a decrease of the micro-RNA called miRNA-150. This miRNA is found in higher concentrations in non-classical monocytes. It does not directly cause the disease, but it causes the monocyte distribution. The fact that hypomethylating drugs work can now also be explained. Hypomethylating drugs demethylate a certain promotor, which causes the miR-150 concentration to rise and more cells to become non-classical monocytes.

Finally, he talked about the role that the mature cells play. The granulocytes produce IL-6, which causes more granulocyte and monocyte production, causing a negative feedback loop. Also, the granulocytes seem to produce a gene that stop monocytes from differentiating into macrophages.

I did find this talk to be very interesting, although a bit difficult, since I did not completely knew the process of hematopoiesis by heart. It was quite confronting how little we know about the disease, and how complicated it is. The most confronting still was that if you do not belong to the 40% of the population that happens to be a responder, you are completely out of options for treatment.

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