Dark selection in CMML

One more year one more IMO Workshop. This year our group worked on CMML or Chronic MyeloMonocytic Leukemia, a relatively rare blood cancer. As usual in IMO workshops our team included clinical (physician and malignant hematology specialist Eric Padron), cancer biologists (Andriy Marusyk and Daria Miroshnychenko) and mathematical modelers from Moffitt, Cleveland Clinic, Oxford, Yale and Harvard. A crack team of interdisciplinary researchers that I was lucky to be part of.

The JAK pathway is considered a driver of CMML and fortunately a drug known as ruxolitinibruxolitinib can target cells whose growth is driven by JAK. Unfortunately, as it is the case with most targeted treatments, ruxolitinib quickly leads to the emergence of resistance and relapse. While this is not entirely surprising, the interesting bit is that neither allele frequency nor tumor burden are impacted by the treatment. What exactly drives ruxolitinib resistance?

Team member Artem Kaznatcheev has written about the basis of our project before so please start by taking a look there. Our group produced a suite of models where we consider three distinct possibilities: that there is a subtle Darwinian selection force impacting proliferation rates, that a (provocatively named) Lamarckian force is driving resistance or that non cell-autonomous mechanisms are in place. We clearly thought of something that resonated with the workshop judges as we were awarded a pilot grant to test this experimentally so stay tuned.

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