{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T13:55:48Z","timestamp":1693576548760},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100009934","name":"E\u00f6tv\u00f6s Lor\u00e1nd University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009934","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Almost all cancer types share the hallmarks of cancer and a similar tumor formation: fueled by stochastic mutations in somatic cells. In case of chronic myeloid leukemia (CML), this evolutionary process can be tracked from an asymptomatic long-lasting chronic phase to a final rapidly evolving blast phase. Somatic evolution in CML occurs in the context of healthy blood production, a hierarchical process of cell division; initiated by stem cells that self-renew and differentiate to produce mature blood cells. Here we introduce a general model of hierarchical cell division explaining the particular progression of CML as resulting from the structure of the hematopoietic system. Driver mutations confer a growth advantage to the cells carrying them, for instance, the <jats:italic>BCR::ABL1<\/jats:italic> gene, which also acts as a marker for CML. We investigated the relation of the <jats:italic>BCR::ABL1<\/jats:italic> mutation strength to the hematopoietic stem cell division rate by employing computer simulations and fitting the model parameters to the reported median duration for the chronic and accelerated phases. Our results demonstrate that driver mutations (additional to the <jats:italic>BCR::ABL1<\/jats:italic> mutation) are necessary to explain CML progression if stem cells divide sufficiently slowly. We observed that the number of mutations accumulated by cells at the more differentiated levels of the hierarchy is not affected by driver mutations present in the stem cells. Our results shed light on somatic evolution in a hierarchical tissue and show that the clinical hallmarks of CML progression result from the structural characteristics of blood production.<\/jats:p>","DOI":"10.1038\/s41598-023-32400-2","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T11:02:40Z","timestamp":1680519760000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The structure of the hematopoietic system can explain chronic myeloid leukemia progression"],"prefix":"10.1038","volume":"13","author":[{"given":"Mario","family":"P\u00e9rez-Jim\u00e9nez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imre","family":"Der\u00e9nyi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gergely J.","family":"Sz\u00f6ll\u0151si","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,4,3]]},"reference":[{"key":"32400_CR1","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1038\/nature03669","volume":"435","author":"F Michor","year":"2005","unstructured":"Michor, F. et al. 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The 5th edition of the World Health Organization classification of haematolymphoid tumours: Myeloid and histiocytic\/dendritic neoplasms. Leukemia 36.7, 1703-1719 (2022).","DOI":"10.1038\/s41375-022-01613-1"},{"key":"32400_CR6","doi-asserted-by":"publisher","first-page":"14545","DOI":"10.1038\/ncomms14545","volume":"8","author":"I Der\u00e9nyi","year":"2017","unstructured":"Der\u00e9nyi, I. & Sz\u00f6ll\u0151si, G. J. Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations. Nat. Commun. 8, 14545 (2017).","journal-title":"Nat. Commun."},{"key":"32400_CR7","doi-asserted-by":"crossref","unstructured":"Abkowitz, J. L., et al. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 100.7, 2665.2667 (2002).","DOI":"10.1182\/blood-2002-03-0822"},{"key":"32400_CR8","doi-asserted-by":"crossref","unstructured":"Lee-Six, H., et al. Population dynamics of normal human blood inferred from somatic mutations. 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