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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\u2019s 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.<\/jats:p>","DOI":"10.1038\/s41375-024-02142-9","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T01:02:25Z","timestamp":1706835745000},"page":"769-780","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia"],"prefix":"10.1038","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8233-5853","authenticated-orcid":false,"given":"David E.","family":"Frankhouser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-159X","authenticated-orcid":false,"given":"Russell C.","family":"Rockne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Uechi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Branciamore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7749-9506","authenticated-orcid":false,"given":"Denis","family":"O\u2019Meally","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3967-2288","authenticated-orcid":false,"given":"Jihyun","family":"Irizarry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8212-3586","authenticated-orcid":false,"given":"Lucy","family":"Ghoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9728-7292","authenticated-orcid":false,"given":"Haris","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0183-4202","authenticated-orcid":false,"given":"Jeffery M.","family":"Trent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2803-4152","authenticated-orcid":false,"given":"Stephen","family":"Forman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5917-2961","authenticated-orcid":false,"given":"Yu-Hsuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-0419","authenticated-orcid":false,"given":"Ya-Huei","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4703-7524","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3983-5908","authenticated-orcid":false,"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"2142_CR1","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1016\/S0140-6736(21)01204-6","volume":"398","author":"J Cortes","year":"2021","unstructured":"Cortes J, Pavlovsky C, Sau\u00dfele S. 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