{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:02:15Z","timestamp":1793394135883,"version":"4.5.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100005189","name":"Leukemia and Lymphoma Society","doi-asserted-by":"publisher","award":["Scholar to Simona Colla"],"award-info":[{"award-number":["Scholar to Simona Colla"]}],"id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P50 CA100632"],"award-info":[{"award-number":["P50 CA100632"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008884","name":"Edward P. Evans Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100008884","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.<\/jats:p>","DOI":"10.1038\/s41591-022-01696-4","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T12:18:55Z","timestamp":1646309935000},"page":"557-567","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy"],"prefix":"10.1038","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8354-3139","authenticated-orcid":false,"given":"Irene","family":"Ganan-Gomez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6260-0787","authenticated-orcid":false,"given":"Feiyang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Montalban-Bravo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natthakan","family":"Thongon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Marchica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Richard-Carpentier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6024-1613","authenticated-orcid":false,"given":"Kelly","family":"Chien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6006-8961","authenticated-orcid":false,"given":"Ganiraju","family":"Manyam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Alfonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaitong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3130-3613","authenticated-orcid":false,"given":"Caleb","family":"Class","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7829-5249","authenticated-orcid":false,"given":"Rashmi","family":"Kanagal-Shamanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin P.","family":"Ingram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamini","family":"Ogoti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-3202","authenticated-orcid":false,"given":"Sanam","family":"Loghavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Lockyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Cambo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8100-8554","authenticated-orcid":false,"given":"Muharrem","family":"Muftuoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7027-7978","authenticated-orcid":false,"given":"Sarah","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-4378","authenticated-orcid":false,"given":"Vera","family":"Adema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-8784","authenticated-orcid":false,"given":"Michael","family":"McLellan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Garza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Marchesini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3457-3774","authenticated-orcid":false,"given":"Nicola","family":"Giuliani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9355-9564","authenticated-orcid":false,"given":"Matteo","family":"Pellegrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-0802","authenticated-orcid":false,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7547-5789","authenticated-orcid":false,"given":"Jason","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-0533","authenticated-orcid":false,"given":"Ziyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8027-9659","authenticated-orcid":false,"given":"Koichi","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel D.","family":"Leverson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Bueso-Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1144-1958","authenticated-orcid":false,"given":"Michael","family":"Andreeff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Clise-Dwyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3631-2482","authenticated-orcid":false,"given":"Guillermo","family":"Garcia-Manero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6583-8910","authenticated-orcid":false,"given":"Simona","family":"Colla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"1696_CR1","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1182\/blood-2011-12-399683","volume":"120","author":"B Will","year":"2012","unstructured":"Will, B. et al. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood 120, 2076\u20132086 (2012).","journal-title":"Blood"},{"key":"1696_CR2","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1016\/j.ccr.2014.03.036","volume":"25","author":"PS Woll","year":"2014","unstructured":"Woll, P. S. et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 25, 794\u2013808 (2014).","journal-title":"Cancer Cell"},{"key":"1696_CR3","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1182\/blood-2017-03-776070","volume":"130","author":"T Mortera-Blanco","year":"2017","unstructured":"Mortera-Blanco, T. et al. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells. Blood 130, 881\u2013890 (2017).","journal-title":"Blood"},{"key":"1696_CR4","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1182\/blood-2016-03-707745","volume":"129","author":"V Chesnais","year":"2017","unstructured":"Chesnais, V. et al. Architectural and functional heterogeneity of hematopoietic stem\/progenitor cells in non-del(5q) myelodysplastic syndromes. Blood 129, 484\u2013496 (2017).","journal-title":"Blood"},{"key":"1696_CR5","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/nrc.2016.112","volume":"17","author":"AS Sperling","year":"2017","unstructured":"Sperling, A. S., Gibson, C. J. & Ebert, B. L. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat. Rev. Cancer 17, 5\u201319 (2017).","journal-title":"Nat. Rev. Cancer"},{"key":"1696_CR6","doi-asserted-by":"publisher","first-page":"3830","DOI":"10.1002\/cncr.25247","volume":"116","author":"E Jabbour","year":"2010","unstructured":"Jabbour, E. et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 116, 3830\u20133834 (2010).","journal-title":"Cancer"},{"key":"1696_CR7","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1200\/JCO.2011.35.8135","volume":"29","author":"T Prebet","year":"2011","unstructured":"Prebet, T. et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J. Clin. Oncol. 29, 3322\u20133327 (2011).","journal-title":"J. Clin. Oncol."},{"key":"1696_CR8","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1056\/NEJMoa1106968","volume":"366","author":"MJ Walter","year":"2012","unstructured":"Walter, M. J. et al. Clonal architecture of secondary acute myeloid leukemia. N. Engl. J. Med. 366, 1090\u20131098 (2012).","journal-title":"N. Engl. J. Med."},{"key":"1696_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15099","volume":"8","author":"P da Silva-Coelho","year":"2017","unstructured":"da Silva-Coelho, P. et al. Clonal evolution in myelodysplastic syndromes. Nat. Commun. 8, 15099 (2017).","journal-title":"Nat. Commun."},{"key":"1696_CR10","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/ng.3742","volume":"49","author":"H Makishima","year":"2017","unstructured":"Makishima, H. et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat. Genet. 49, 204\u2013212 (2017).","journal-title":"Nat. Genet."},{"key":"1696_CR11","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/s41591-018-0267-4","volume":"25","author":"J Chen","year":"2019","unstructured":"Chen, J. et al. Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level. Nat. Med. 25, 103\u2013110 (2019).","journal-title":"Nat. Med."},{"key":"1696_CR12","doi-asserted-by":"publisher","first-page":"3011","DOI":"10.1073\/pnas.1222861110","volume":"110","author":"WW Pang","year":"2013","unstructured":"Pang, W. W. et al. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc. Natl Acad. Sci. USA 110, 3011\u20133016 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1696_CR13","doi-asserted-by":"publisher","first-page":"3699","DOI":"10.1182\/blood-2014-01-549527","volume":"124","author":"FC Lin","year":"2014","unstructured":"Lin, F. C. et al. IFN-gamma causes aplastic anemia by altering hematopoietic stem\/progenitor cell composition and disrupting lineage differentiation. Blood 124, 3699\u20133708 (2014).","journal-title":"Blood"},{"key":"1696_CR14","doi-asserted-by":"publisher","first-page":"aab2116","DOI":"10.1126\/science.aab2116","volume":"351","author":"F Notta","year":"2016","unstructured":"Notta, F. et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 351, aab2116 (2016).","journal-title":"Science"},{"key":"1696_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10291-0","volume":"10","author":"D Pellin","year":"2019","unstructured":"Pellin, D. et al. A comprehensive single cell transcriptional landscape of human hematopoietic progenitors. Nat. Commun. 10, 2395 (2019).","journal-title":"Nat. Commun."},{"key":"1696_CR16","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.ccr.2010.12.012","volume":"19","author":"N Goardon","year":"2011","unstructured":"Goardon, N. et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138\u2013152 (2011).","journal-title":"Cancer Cell"},{"key":"1696_CR17","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nbt.2859","volume":"32","author":"C Trapnell","year":"2014","unstructured":"Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381\u2013386 (2014).","journal-title":"Nat. Biotechnol."},{"key":"1696_CR18","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/nmeth.2883","volume":"11","author":"A Roth","year":"2014","unstructured":"Roth, A. et al. PyClone: statistical inference of clonal population structure in cancer. Nat. Methods 11, 396\u2013398 (2014).","journal-title":"Nat. Methods"},{"key":"1696_CR19","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1038\/leu.2012.312","volume":"27","author":"C Craddock","year":"2013","unstructured":"Craddock, C. et al. Azacitidine fails to eradicate leukemic stem\/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 27, 1028\u20131036 (2013).","journal-title":"Leukemia"},{"key":"1696_CR20","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.ccell.2015.04.007","volume":"27","author":"S Colla","year":"2015","unstructured":"Colla, S. et al. Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell 27, 644\u2013657 (2015).","journal-title":"Cancer Cell"},{"key":"1696_CR21","doi-asserted-by":"publisher","first-page":"2182","DOI":"10.1038\/s41375-021-01265-7","volume":"35","author":"U Platzbecker","year":"2021","unstructured":"Platzbecker, U., Kubasch, A. S., Homer-Bouthiette, C. & Prebet, T. Current challenges and unmet medical needs in myelodysplastic syndromes. Leukemia 35, 2182\u20132198 (2021).","journal-title":"Leukemia"},{"key":"1696_CR22","doi-asserted-by":"publisher","first-page":"2548","DOI":"10.1073\/pnas.1324297111","volume":"111","author":"MR Corces-Zimmerman","year":"2014","unstructured":"Corces-Zimmerman, M. R., Hong, W. J., Weissman, I. L., Medeiros, B. C. & Majeti, R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc. Natl Acad. Sci. USA 111, 2548\u20132553 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1696_CR23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1084\/jem.191.2.253","volume":"191","author":"J Domen","year":"2000","unstructured":"Domen, J., Cheshier, S. H. & Weissman, I. L. The role of apoptosis in the regulation of hematopoietic stem cells: overexpression of Bcl-2 increases both their number and repopulation potential. J. Exp. Med. 191, 253\u2013264 (2000).","journal-title":"J. Exp. Med."},{"key":"1696_CR24","doi-asserted-by":"publisher","first-page":"6626","DOI":"10.1182\/blood-2010-12-326710","volume":"118","author":"M Nakagawa","year":"2011","unstructured":"Nakagawa, M. et al. AML1\/RUNX1 functions as a cytoplasmic attenuator of NF-kappa B signaling in the repression of myeloid tumors. Blood 118, 6626\u20136637 (2011).","journal-title":"Blood"},{"key":"1696_CR25","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.stem.2019.05.019","volume":"25","author":"M Yamashita","year":"2019","unstructured":"Yamashita, M. & Passegue, E. TNF-\u03b1 coordinates hematopoietic stem cell survival and myeloid regeneration. Cell Stem Cell 25, 357\u2013372 (2019).","journal-title":"Cell Stem Cell"},{"key":"1696_CR26","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/leu.2009.296","volume":"24","author":"A Matsuoka","year":"2010","unstructured":"Matsuoka, A. et al. Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis. Leukemia 24, 748\u2013755 (2010).","journal-title":"Leukemia"},{"key":"1696_CR27","doi-asserted-by":"publisher","first-page":"4642","DOI":"10.1200\/JCO.2003.04.036","volume":"21","author":"BD Cheson","year":"2003","unstructured":"Cheson, B. D. et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J. Clin. Oncol. 21, 4642\u20134649 (2003).","journal-title":"J. Clin. Oncol."},{"key":"1696_CR28","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1182\/blood-2005-10-4149","volume":"108","author":"BD Cheson","year":"2006","unstructured":"Cheson, B. D. et al. Clinical application and proposal for modification of the International Working Group response criteria in myelodysplasia. Blood 108, 419\u2013425 (2006).","journal-title":"Blood"},{"key":"1696_CR29","doi-asserted-by":"publisher","first-page":"2705","DOI":"10.1182\/blood-2014-06-582809","volume":"124","author":"R Bejar","year":"2014","unstructured":"Bejar, R. et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124, 2705\u20132712 (2014).","journal-title":"Blood"},{"key":"1696_CR30","doi-asserted-by":"publisher","first-page":"14172","DOI":"10.18632\/oncotarget.7290","volume":"7","author":"K Takahashi","year":"2016","unstructured":"Takahashi, K. et al. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. Oncotarget 7, 14172\u201314187 (2016).","journal-title":"Oncotarget"},{"key":"1696_CR31","doi-asserted-by":"publisher","first-page":"4971","DOI":"10.1182\/blood-2011-11-389957","volume":"119","author":"Y Chen","year":"2012","unstructured":"Chen, Y. et al. Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment. Blood 119, 4971\u20134980 (2012).","journal-title":"Blood"},{"key":"1696_CR32","unstructured":"R Core Team. R Foundation for Statistical Computing. R: A language and environment for statistical computing http:\/\/www.R-project.org\/ (2016)."},{"key":"1696_CR33","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1080\/01621459.1963.10500845","volume":"58","author":"JH Ward","year":"1963","unstructured":"Ward, J. H. Hierarchical grouping to optimize an objective function. J. Am. Stat. Assoc. 58, 236\u2013244 (1963).","journal-title":"J. Am. Stat. Assoc."},{"key":"1696_CR34","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1002\/gene.10161","volume":"34","author":"P Georgiades","year":"2002","unstructured":"Georgiades, P. et al. VavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages. Genesis 34, 251\u2013256 (2002).","journal-title":"Genesis"},{"key":"1696_CR35","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ccr.2011.06.001","volume":"20","author":"K Moran-Crusio","year":"2011","unstructured":"Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11\u201324 (2011).","journal-title":"Cancer Cell"},{"key":"1696_CR36","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1126\/science.7660125","volume":"269","author":"R K\u00fchn","year":"1995","unstructured":"K\u00fchn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427\u20131429 (1995).","journal-title":"Science"},{"key":"1696_CR37","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.ccell.2015.04.006","volume":"27","author":"E Kim","year":"2015","unstructured":"Kim, E. et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell 27, 617\u2013630 (2015).","journal-title":"Cancer Cell"},{"key":"1696_CR38","doi-asserted-by":"publisher","first-page":"3765","DOI":"10.1242\/dev.094961","volume":"140","author":"J Tober","year":"2013","unstructured":"Tober, J., Yzaguirre, A. D., Piwarzyk, E. & Speck, N. A. Distinct temporal requirements for Runx1 in hematopoietic progenitors and stem cells. Development 140, 3765\u20133776 (2013).","journal-title":"Development"},{"key":"1696_CR39","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.ccell.2015.04.008","volume":"27","author":"CL Shirai","year":"2015","unstructured":"Shirai, C. L. et al. Mutant U2AF1 expression alters hematopoiesis and pre-mRNA splicing in vivo. Cancer Cell 27, 631\u2013643 (2015).","journal-title":"Cancer Cell"},{"key":"1696_CR40","volume":"7","author":"C Shyr","year":"2014","unstructured":"Shyr, C. et al. FLAGS, frequently mutated genes in public exomes. BMC Med. Genet. 7, 64 (2014).","journal-title":"BMC Med. Genet."},{"key":"1696_CR41","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/j.cell.2018.07.034","volume":"174","author":"MH Bailey","year":"2018","unstructured":"Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 174, 1034\u20131035 (2018).","journal-title":"Cell"},{"key":"1696_CR42","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1038\/nbt.2696","volume":"31","author":"GM Frampton","year":"2013","unstructured":"Frampton, G. M. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol. 31, 1023\u20131031 (2013).","journal-title":"Nat. Biotechnol."},{"key":"1696_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4156","volume":"5","author":"KL Kanchi","year":"2014","unstructured":"Kanchi, K. L. et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat. Commun. 5, 3156 (2014).","journal-title":"Nat. Commun."},{"key":"1696_CR44","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/nature12634","volume":"502","author":"C Kandoth","year":"2013","unstructured":"Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333\u2013339 (2013).","journal-title":"Nature"},{"key":"1696_CR45","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nature12912","volume":"505","author":"MS Lawrence","year":"2014","unstructured":"Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495\u2013501 (2014).","journal-title":"Nature"},{"key":"1696_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10086","volume":"6","author":"C Lu","year":"2015","unstructured":"Lu, C. et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat. Commun. 6, 10086 (2015).","journal-title":"Nat. Commun."},{"key":"1696_CR47","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jmoldx.2013.08.004","volume":"16","author":"CC Pritchard","year":"2014","unstructured":"Pritchard, C. C. et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation and gene rearrangement in clinical cancer specimens. J. Mol. Diagnostics 16, 56\u201367 (2014).","journal-title":"J. Mol. Diagnostics"},{"key":"1696_CR48","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1038\/nature12981","volume":"505","author":"N Rahman","year":"2014","unstructured":"Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302\u2013308 (2014).","journal-title":"Nature"},{"key":"1696_CR49","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/gim.2013.92","volume":"15","author":"HL Rehm","year":"2013","unstructured":"Rehm, H. L. et al. ACMG clinical laboratory standards for next-generation sequencing. Genet. Med. 15, 733\u2013747 (2013).","journal-title":"Genet. Med."},{"key":"1696_CR50","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1126\/science.1235122","volume":"339","author":"B Vogelstein","year":"2013","unstructured":"Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546\u20131558 (2013).","journal-title":"Science"},{"key":"1696_CR51","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1586\/14737159.2016.1142374","volume":"16","author":"R Kanagal-Shamanna","year":"2016","unstructured":"Kanagal-Shamanna, R. et al. Principles of analytical validation of next-generation sequencing based mutational analysis for hematologic neoplasms in a CLIA-certified laboratory. Expert Rev. Mol. Diagn. 16, 461\u2013472 (2016).","journal-title":"Expert Rev. Mol. Diagn."},{"key":"1696_CR52","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1182\/bloodadvances.2018026989","volume":"3","author":"G Montalban-Bravo","year":"2019","unstructured":"Montalban-Bravo, G. et al. NPM1 mutations define a specific subgroup of MDS and MDS\/MPN patients with favorable outcomes with intensive chemotherapy. Blood Adv. 3, 922\u2013933 (2019).","journal-title":"Blood Adv."},{"key":"1696_CR53","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/nmeth.2883","volume":"11","author":"A Roth","year":"2014","unstructured":"Roth, A. et al. PyClone: statistical inference of clonal population structure in cancer. Nat. Methods 11, 396\u2013398 (2014).","journal-title":"Nat. Methods"},{"key":"1696_CR54","doi-asserted-by":"publisher","unstructured":"Krzywinski, M. I. et al. Circos: an information aesthetic for comparative genomics. Genome Res. https:\/\/doi.org\/10.1101\/gr.092759.109 (2009).","DOI":"10.1101\/gr.092759.109"},{"key":"1696_CR55","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/S1470-2045(16)30626-X","volume":"18","author":"K Takahashi","year":"2017","unstructured":"Takahashi, K. et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case\u2013control study. Lancet Oncol. 18, 100\u2013111 (2017).","journal-title":"Lancet Oncol."},{"key":"1696_CR56","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","volume":"177","author":"T Stuart","year":"2019","unstructured":"Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888\u20131902 (2019).","journal-title":"Cell"},{"key":"1696_CR57","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nbt.2859","volume":"32","author":"C Trapnell","year":"2014","unstructured":"Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381\u2013386 (2014).","journal-title":"Nat. Biotechnol."},{"key":"1696_CR58","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq\u2014a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169 (2015).","journal-title":"Bioinformatics"},{"key":"1696_CR59","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"1696_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6","volume":"10","author":"Y Zhou","year":"2019","unstructured":"Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).","journal-title":"Nat. Commun."},{"key":"1696_CR61","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/cyto.a.22625","volume":"87","author":"S Van Gassen","year":"2015","unstructured":"Van Gassen, S. et al. FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A 87, 636\u2013645 (2015).","journal-title":"Cytometry A"},{"key":"1696_CR62","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","volume":"26","author":"MD Wilkerson","year":"2010","unstructured":"Wilkerson, M. D. & Hayes, D. N. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 26, 1572\u20131573 (2010).","journal-title":"Bioinformatics"},{"key":"1696_CR63","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12859-021-04054-2","volume":"22","author":"Y Dai","year":"2021","unstructured":"Dai, Y. et al. CytoTree: an R\/Bioconductor package for analysis and visualization of flow and mass cytometry data. BMC Bioinformatics 22, 138 (2021).","journal-title":"BMC Bioinformatics"}],"updated-by":[{"DOI":"10.1038\/s41591-022-01827-x","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000}}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-022-01696-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-022-01696-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-022-01696-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T07:17:53Z","timestamp":1651216673000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-022-01696-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3]]},"references-count":63,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,3]]}},"alternative-id":["1696"],"URL":"https:\/\/doi.org\/10.1038\/s41591-022-01696-4","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3]]},"assertion":[{"value":"10 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2022","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41591-022-01827-x","URL":"https:\/\/doi.org\/10.1038\/s41591-022-01827-x","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.C. and M.A. report research funding from AbbVie and Amgen. J.P.I. and J.D.L. worked at AbbVie at the time of the study; G.G.-M. reports clinical funding from AbbVie and Amgen. All other authors report no competing interests related to this study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}