Dr. John Dick gave a great talk yesterday on cancer stem cells here at ISSCR 2016. Below I summarize his talk and as always with these meeting blogs, the post is not polished and is more of a stream of the speaker’s main points. He started out broadly with a nice introduction to this area of research.
There’s a lot of controversy around cancer stem cells (CSC). How many tumors have CSCs? How different are cells within the same tumor?
The normal hierarchical organization of hematopoiesis is disrupted in AML. Are CSC properties clinically relevant in leukemia?
Here the focus is on leukemic stem cells (LSC). If a patient’s cells can engraft a mouse then that patient has much worse survival. This engraftment predicts relapse. They have developed a LSC prognostic score. NMP1mut FLT3-ITD neg cells are mentioned. miRNA signatures and epigenetics matter for survival. Big picture conclusion: stem cell properties are very important to the disease.
More genetic studies. Branching tumor evolution during leukemia development: what is the role of stem cells? They did deep targeted sequencing of the genes known to be important for AML. They discovered a common ancestor gene commonly mutated in AML. (Shlush, Nature 2014). DNMT3a mutation was present in the common ancestor cell. Leukemia blasts can have the DNMT3a and NPM1C alleles, but many only have one marker (suggesting clonal evolution).
This raises many interesting questions.
Where does relapse come from? What is cellular origin? Did the chemo induce changes? Or are there residual cells that then spur a tumor comeback?
There’s no definitive marker for LSC.
Evidence of a long evolution in the preleukemic phase. One model is that relapse originates from rare LSC that evolve before diagnosis and survive therapy.
A fascinating point–cells that preferentially grow in the mouse xenograft are not the predominant one in the patient at presentation but rather the ones that will later kill the patient through relapse. Another model is that relapse stems from a rare CD33+ subset.
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