TY - JOUR T1 - Dark selection for JAK/STAT-inhibitor resistance in chronic myelomonocytic leukemia JF - bioRxiv DO - 10.1101/211151 SP - 211151 AU - Artem Kaznatcheev AU - David Robert Grimes AU - Robert Vander Velde AU - Vincent Cannataro AU - Etienne Baratchart AU - Andrew Dhawan AU - Lin Liu AU - Daria Myroshnychenko AU - Jake P. Taylor-King AU - Nara Yoon AU - Eric Padron AU - Andriy Marusyk AU - David Basanta Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/10/30/211151.abstract N2 - Acquired therapy resistance to cancer treatment is a common and serious clinical problem. The classic U-shape model for the emergence of resistance supposes that: (1) treatment changes the selective pressure on the treatment-naive tumour; (2) this shifting pressure creates a proliferative or survival difference between sensitive cancer cells and either an existing or de novo mutant; (3) the resistant cells then out-compete the sensitive cells and – if further interventions (like drug holidays or new drugs or dosage changes) are not pursued – take over the tumour: returning it to a state dangerous to the patient. The emergence of ruxolitinib resistance in chronic myelomonocytic leukemia (CMML) seems to challenge the classic model: we see the global properties of resistance, but not the drastic change in clonal architecture expected with the selection bottleneck. To study this, we explore three population-level models as alternatives to the classic model of resistance. These three effective models are designed in such a way that they are distinguishable based on limited experimental data on the time-progression of resistance in CMML. We also propose a candidate reductive implementation of the proximal cause of resistance to ground these effective theories. With these reductive implementations in mind, we also explore the impact of oxygen diffusion and spatial structure more generally on the dynamics of CMML in the bone marrow concluding that, even small fluctuations in oxygen availability can seriously impact the efficacy of ruxolitinib. Finally, we look at the ability of spatially distributed cytokine signaling feedback loops to produce a relapse in symptoms similar to what we observe in the clinic. ER -