1. State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia
- Author
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Frankhouser, David E, Frankhouser, David E, Rockne, Russell C, Uechi, Lisa, Zhao, Dandan, Branciamore, Sergio, O’Meally, Denis, Irizarry, Jihyun, Ghoda, Lucy, Ali, Haris, Trent, Jeffery M, Forman, Stephen, Fu, Yu-Hsuan, Kuo, Ya-Huei, Zhang, Bin, Marcucci, Guido, Frankhouser, David E, Frankhouser, David E, Rockne, Russell C, Uechi, Lisa, Zhao, Dandan, Branciamore, Sergio, O’Meally, Denis, Irizarry, Jihyun, Ghoda, Lucy, Ali, Haris, Trent, Jeffery M, Forman, Stephen, Fu, Yu-Hsuan, Kuo, Ya-Huei, Zhang, Bin, and Marcucci, Guido
- Abstract
Chronic myeloid leukemia (CML) is initiated and maintained by BCR::ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). TKIs can induce long-term remission but are also 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. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR::ABL-inducible transgenic mice and wild-type controls. From the transcriptome, we constructed a CML state-space and a three-well leukemogenic potential landscape. The potential's stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemia; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as drivers of disease transition. Re-introduction of tetracycline to silence the BCR::ABL gene returned diseased mice transcriptomes to a near healthy state, without reaching it, suggesting parts of the transition are irreversible. TKI only reverted the transcriptome to an intermediate disease state, without approaching a state of health; disease relapse occurred soon after treatment. Using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention, before phenotypic changes become detectable.
- Published
- 2024