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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 statespace 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 even before phenotypic changes become detectable.<\/jats:p>","DOI":"10.1101\/2023.10.11.561908","type":"posted-content","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T14:55:41Z","timestamp":1697122541000},"source":"Crossref","is-referenced-by-count":2,"title":["State-transition Modeling of Blood Transcriptome Predicts Disease Evolution and Treatment Response in Chronic Myeloid Leukemia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8233-5853","authenticated-orcid":false,"given":"David E.","family":"Frankhouser","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-159X","authenticated-orcid":false,"given":"Russell C.","family":"Rockne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8215-6938","authenticated-orcid":false,"given":"Lisa","family":"Uechi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2556-8765","authenticated-orcid":false,"given":"Sergio","family":"Branciamore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7749-9506","authenticated-orcid":false,"given":"Denis","family":"O\u2019Meally","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihyun","family":"Irizarry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8212-3586","authenticated-orcid":false,"given":"Lucy","family":"Ghoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haris","family":"Ali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0183-4202","authenticated-orcid":false,"given":"Jeffery M.","family":"Trent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Forman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Hsuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-0419","authenticated-orcid":false,"given":"Ya-Huei","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3983-5908","authenticated-orcid":false,"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023121207201030000_2023.10.11.561908v2.1","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1016\/S0140-6736(21)01204-6","article-title":"Chronic myeloid leukaemia","volume":"398","year":"2021","journal-title":"Lancet (London, England)"},{"key":"2023121207201030000_2023.10.11.561908v2.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104053441409"},{"key":"2023121207201030000_2023.10.11.561908v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/nm0596-561"},{"key":"2023121207201030000_2023.10.11.561908v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35677-5"},{"key":"2023121207201030000_2023.10.11.561908v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4399"},{"key":"2023121207201030000_2023.10.11.561908v2.6","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-021-02422-6"},{"key":"2023121207201030000_2023.10.11.561908v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70233-3"},{"key":"2023121207201030000_2023.10.11.561908v2.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-483750"},{"key":"2023121207201030000_2023.10.11.561908v2.9","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-0354"},{"key":"2023121207201030000_2023.10.11.561908v2.10","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1126\/sciadv.abj1664","article-title":"Dynamic patterns of microRNA expression during acute myeloid leukemia state-transition","volume":"8","year":"2022","journal-title":"Sci. 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