{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T10:00:35Z","timestamp":1794650435083,"version":"4.9.1"},"reference-count":115,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"2","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>A major obstacle in the treatment of acute myeloid leukemia (AML) is refractory disease or relapse after achieving remission. The latter arises from a few therapy-resistant cells within minimal residual disease (MRD). Resistant cells with long-term self-renewal capacity that drive clonal outgrowth are referred to as leukemic stem cells (LSC). The cancer stem cell concept considers LSC as relapse-initiating cells residing at the top of each genetically defined AML subclone forming epigenetically controlled downstream hierarchies. LSC display significant phenotypic and epigenetic plasticity, particularly in response to therapy stress, which results in various mechanisms mediating treatment resistance. Given the inherent chemotherapy resistance of LSC, targeted strategies must be incorporated into first-line regimens to prevent LSC-mediated AML relapse. The combination of venetoclax and azacitidine is a promising current strategy for the treatment of AML LSC. Nevertheless, the selection of patients who would benefit either from standard chemotherapy or venetoclax + azacitidine treatment in first-line therapy has yet to be established and the mechanisms of resistance still need to be discovered and overcome. Clinical trials are currently underway that investigate LSC susceptibility to first-line therapies. The era of single-cell multi-omics has begun to uncover the complex clonal and cellular architectures and associated biological networks. This should lead to a better understanding of the highly heterogeneous AML at the inter- and intra-patient level and identify resistance mechanisms by longitudinal analysis of patients\u2019 samples. This review discusses LSC biology and associated resistance mechanisms, potential therapeutic LSC vulnerabilities and current clinical trial activities.<\/jats:p>","DOI":"10.3324\/haematol.2022.280800","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T04:19:41Z","timestamp":1675225181000},"page":"353-366","source":"Crossref","is-referenced-by-count":270,"title":["Leukemic stem cells and therapy resistance in acute myeloid leukemia"],"prefix":"10.3324","volume":"108","author":[{"given":"Patrick","family":"Stelmach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Trumpp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2023,2,1]]},"reference":[{"key":"43857","doi-asserted-by":"crossref","unstructured":"Papaemmanuil E, Gerstung M, Bullinger L. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016; 374(23):2209-2221.","DOI":"10.1056\/NEJMoa1516192"},{"key":"43858","doi-asserted-by":"crossref","unstructured":"Short NJ, Konopleva M, Kadia TM. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov. 2020; 10(4):506-525.","DOI":"10.1158\/2159-8290.CD-19-1011"},{"key":"43859","doi-asserted-by":"crossref","unstructured":"Dohner H, Estey E, Grimwade D. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424-447.","DOI":"10.1182\/blood-2016-08-733196"},{"key":"43860","doi-asserted-by":"crossref","unstructured":"Jongen-Lavrencic M, Grob T, Hanekamp D. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018; 378(13):1189-1199.","DOI":"10.1056\/NEJMoa1716863"},{"key":"43861","doi-asserted-by":"crossref","unstructured":"Trumpp A, Haas S. Cancer stem cells: the adventurous journey from hematopoietic to leukemic stem cells. Cell. 2022; 185(8):1266-1270.","DOI":"10.1016\/j.cell.2022.03.025"},{"key":"43862","doi-asserted-by":"crossref","unstructured":"DiNardo CD, Jonas BA, Pullarkat V. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020; 383(7):617-629.","DOI":"10.1056\/NEJMoa2012971"},{"key":"43863","doi-asserted-by":"crossref","unstructured":"Stahl M, Menghrajani K, Derkach A. Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed\/refractory AML. Blood Adv. 2021; 5(5):1552-1564.","DOI":"10.1182\/bloodadvances.2020003734"},{"key":"43864","doi-asserted-by":"crossref","unstructured":"Haas S, Trumpp A, Milsom MD. Causes and consequences of hematopoietic stem cell heterogeneity. Cell Stem Cell. 2018; 22(5):627-638.","DOI":"10.1016\/j.stem.2018.04.003"},{"key":"43865","doi-asserted-by":"crossref","unstructured":"Laurenti E, Gottgens B. From haematopoietic stem cells to complex differentiation landscapes. Nature. 2018; 553(7689):418-426.","DOI":"10.1038\/nature25022"},{"key":"43866","doi-asserted-by":"crossref","unstructured":"Wilson A, Laurenti E, Oser G. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008; 135(6):1118-1129.","DOI":"10.1016\/j.cell.2008.10.048"},{"key":"43867","doi-asserted-by":"crossref","unstructured":"Cabezas-Wallscheid N, Buettner F, Sommerkamp P. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell. 2017; 169(5):807-823.","DOI":"10.1016\/j.cell.2017.04.018"},{"key":"43868","doi-asserted-by":"crossref","unstructured":"Yamamoto R, Morita Y, Ooehara J. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. 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Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. 2018; 34(5):724-740.","DOI":"10.1016\/j.ccell.2018.10.005"},{"key":"43933","doi-asserted-by":"crossref","unstructured":"Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011; 9(4):298-310.","DOI":"10.1016\/j.stem.2011.09.010"},{"key":"43934","doi-asserted-by":"crossref","unstructured":"Pollyea DA, Stevens BM, Jones CL. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018; 24(12):1859-1866.","DOI":"10.1038\/s41591-018-0233-1"},{"key":"43935","doi-asserted-by":"crossref","unstructured":"Jones CL, Stevens BM, D'Alessandro A. Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II. Blood. 2019; 134(4):389-394.","DOI":"10.1182\/blood.2019898114"},{"key":"43936","doi-asserted-by":"crossref","unstructured":"Widden H, Placzek WJ. The multiple mechanisms of MCL1 in the regulation of cell fate. Commun Biol. 2021; 4(1):1029.","DOI":"10.1038\/s42003-021-02564-6"},{"key":"43937","doi-asserted-by":"crossref","unstructured":"Stevens BM, Jones CL, Pollyea DA. Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat Cancer. 2020; 1(12):1176-1187.","DOI":"10.1038\/s43018-020-00126-z"},{"key":"43938","doi-asserted-by":"crossref","unstructured":"Pei S, Pollyea DA, Gustafson A. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov. 2020; 10(4):536-551.","DOI":"10.1158\/2159-8290.CD-19-0710"},{"key":"43939","doi-asserted-by":"crossref","unstructured":"Moujalled DM, Brown FC, Chua CC. Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia. 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