Chronic myeloid leukemia (CML) is initiated and initially maintained solely by the fusion gene BCR-ABL, encoding a multifaceted chimeric kinase targeted in the clinic with tyrosine kinase inhibitors (TKIs) TKIs are effective in inducing long-term remission, but are also frequently not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. To test our hypothesis, we collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR-ABL-inducible transgenic mice and wild-type controls. Using the time-series bulk RNA-seq analysis to capture a system-wide view of distinct disease states, we identified a single principal component that constructed a CML state-space with a three-well BCR-ABL leukemogenic potential landscape. The potential stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemic transformation; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as disease transition drivers. Re-introduction of tetracyclines to silence the BCR/ABL gene returned diseased mice transcriptomes to a stable state near to health, without reaching it, suggesting partly irreversible transformation changes. TKI treatment only reverted the diseased mice transcriptomes to an earlier disease state, without approaching health; disease relapse occurred soon after treatment completion. Using only the earliest time-point as initial conditions, our parametrized state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention even before phenotypic changes become detectable.