Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
21 Aug 2024
21 Aug 2024
Historique:
received:
03
01
2024
accepted:
17
07
2024
revised:
02
07
2024
medline:
22
8
2024
pubmed:
22
8
2024
entrez:
21
8
2024
Statut:
aheadofprint
Résumé
The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential, repopulation capacity, sensitivity to chemotherapy and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for investigating the LSC compartment and designing combinatorial therapeutic strategies in AML.
Identifiants
pubmed: 39169113
doi: 10.1038/s41375-024-02358-9
pii: 10.1038/s41375-024-02358-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Princess Margaret Cancer Foundation (PMCF)
ID : RN380110 - 409786
Organisme : Canadian Cancer Society Research Institute (Société Canadienne du Cancer)
ID : 706662
Organisme : Leukemia and Lymphoma Society of Canada (Leukemia & Lymphoma Society of Canada)
ID : 1042891
Organisme : Leukemia and Lymphoma Society of Canada (Leukemia & Lymphoma Society of Canada)
ID : 1042891
Informations de copyright
© 2024. The Author(s).
Références
Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011;17:1086–93.
pubmed: 21873988
doi: 10.1038/nm.2415
Ng SWK, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.
pubmed: 27926740
doi: 10.1038/nature20598
van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S, et al. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res. 2005;11:6520–7.
pubmed: 16166428
doi: 10.1158/1078-0432.CCR-05-0468
Gentles AJ, Plevritis SK, Majeti R, Alizadeh AA. Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA. 2010;304:2706–15.
pubmed: 21177505
pmcid: 4089862
doi: 10.1001/jama.2010.1862
Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood. 2017;129:1577–85.
pubmed: 28159741
pmcid: 5364335
doi: 10.1182/blood-2016-10-696054
Benveniste P, Frelin C, Janmohamed S, Barbara M, Herrington R, Hyam D, et al. Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential. Cell Stem Cell. 2010;6:48–58.
pubmed: 20074534
doi: 10.1016/j.stem.2009.11.014
Laurenti E, Frelin C, Xie S, Ferrari R, Dunant CF, Zandi S, et al. CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell. 2015;16:302–13.
pubmed: 25704240
pmcid: 4359055
doi: 10.1016/j.stem.2015.01.017
Notta F, Zandi S, Takayama N, Dobson S, Gan OI, Wilson G, et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2016;351:aab2116.
pubmed: 26541609
doi: 10.1126/science.aab2116
Rodriguez-Fraticelli AE, Weinreb C, Wang S-W, Migueles RP, Jankovic M, Usart M, et al. Single-cell lineage tracing unveils a role for TCF15 in haematopoiesis. Nature. 2020;583:585–9.
pubmed: 32669716
pmcid: 7579674
doi: 10.1038/s41586-020-2503-6
Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333:218–21.
pubmed: 21737740
doi: 10.1126/science.1201219
Kaufmann KB, Zeng AGX, Coyaud E, Garcia-Prat L, Papalexi E, Murison A, et al. A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness. Nat Immunol. 2021;22:723–34.
pubmed: 33958784
doi: 10.1038/s41590-021-00925-1
Kaufmann KB, Zeng AGX, Coyaud E, Garcia-Prat L, Papalexi E, Laurent EMN et al. A distinct subset of human blood stem cells resists regenerative stress to preserve stemness. Soc Sci Res Netw: Rochester, NY, 2020. https://papers.ssrn.com/abstract=3612406 .
Morita K, Wang F, Jahn K, Hu T, Tanaka T, Sasaki Y, et al. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat Commun. 2020;11:5327.
pubmed: 33087716
pmcid: 7577981
doi: 10.1038/s41467-020-19119-8
Schuringa JJ, Bonifer C. Dissecting clonal heterogeneity in AML. Cancer Cell. 2020;38:782–4.
pubmed: 33321087
doi: 10.1016/j.ccell.2020.11.011
Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukemic hematopoietic stem cells in acute leukemia. Nature. 2014;506:328–33.
pubmed: 24522528
pmcid: 4991939
doi: 10.1038/nature13038
Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature. 2011;469:356–61.
pubmed: 21160474
doi: 10.1038/nature09650
Boer de B, Prick J, Pruis MG, Keane P, Imperato MR, Jaques J, et al. Prospective isolation and characterization of genetically and functionally distinct AML subclones. Cancer Cell. 2018;34:674–89.e8.
pubmed: 30245083
doi: 10.1016/j.ccell.2018.08.014
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10.
pubmed: 22237025
pmcid: 3267864
doi: 10.1038/nature10738
Miles LA, Bowman RL, Merlinsky TR, Csete IS, Ooi AT, Durruthy-Durruthy R, et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature. 2020;587:477–82.
pubmed: 33116311
pmcid: 7677169
doi: 10.1038/s41586-020-2864-x
Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5:738–43.
pubmed: 15170211
doi: 10.1038/ni1080
Pollyea DA, Jordan CT. Therapeutic targeting of acute myeloid leukemia stem cells. Blood. 2017;129:1627–35.
pubmed: 28159738
doi: 10.1182/blood-2016-10-696039
Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–74.
pubmed: 16998484
doi: 10.1038/nm1483
Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell. 2009;5:31–42.
pubmed: 19570512
doi: 10.1016/j.stem.2009.04.018
Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–99.
pubmed: 19632179
pmcid: 2726837
doi: 10.1016/j.cell.2009.05.045
Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, et al. Identification of Therapeutic Targets for Quiescent, Chemotherapy-Resistant Human Leukemia Stem Cells. Sci Transl Med. 2010;2:17ra9.
pubmed: 20371479
pmcid: 3005290
doi: 10.1126/scitranslmed.3000349
Laverdière I, Boileau M, Neumann AL, Frison H, Mitchell A, Ng SWK, et al. Leukemic stem cell signatures identify novel therapeutics targeting acute myeloid leukemia. Blood Cancer J. 2018;8:1–16.
doi: 10.1038/s41408-018-0087-2
Jung N, Dai B, Gentles AJ, Majeti R, Feinberg AP. An LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis. Nat Commun. 2015;6:8489.
pubmed: 26444494
doi: 10.1038/ncomms9489
Corces MR, Buenrostro JD, Wu B, Greenside PG, Chan SM, Koenig JL, et al. Lineage-specific and single cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat Genet. 2016;48:1193–203.
pubmed: 27526324
pmcid: 5042844
doi: 10.1038/ng.3646
Murphy T, Ng SWK, Zhang T, King I, Arruda A, Claudio JO, et al. Trial in progress: feasibility and validation study of the LSC17 score in acute myeloid leukemia patients. Blood. 2019;134:2682.
doi: 10.1182/blood-2019-130532
Duployez N, Marceau-Renaut A, Villenet C, Petit A, Rousseau A, Ng SWK, et al. The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia. Leukemia. 2019;33:348–57.
pubmed: 30089916
doi: 10.1038/s41375-018-0227-5
Ng SW, Murphy T, King I, Zhang T, Mah M, Lu Z et al. A clinical laboratory-developed LSC17 stemness score assay for rapid risk assessment of acute myeloid leukemia patients. Blood Adv. 2021. https://doi.org/10.1182/bloodadvances.2021005741 .
van Galen, Hovestadt P, Wadsworth V, Ii MH, Hughes TK, Griffin GK, et al. Single-cell RNA-Seq reveals AML hierarchies relevant to disease progression and immunity. Cell. 2019;176:1265–81.e24.
pubmed: 30827681
pmcid: 6515904
doi: 10.1016/j.cell.2019.01.031
Zeng AGX, Bansal S, Jin L, Mitchell A, Chen WC, Abbas HA, et al. A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia. Nat Med. 2022;28:1212–23.
pubmed: 35618837
doi: 10.1038/s41591-022-01819-x
Boutzen H, Madani Tonekaboni SA, Chan-Seng-Yue M, Murison A, Takayama N, Mbong N, et al. A primary hierarchically organized patient-derived model enables in depth interrogation of stemness driven by the coding and non-coding genome. Leukemia. 2022;36:2690–704.
pubmed: 36131042
pmcid: 9613464
doi: 10.1038/s41375-022-01697-9
Kan WL, Dhagat U, Kaufmann KB, Hercus TR, Nero TL, Zeng AGX, et al. Distinct assemblies of heterodimeric cytokine receptors govern stemness programs in leukemia. Cancer Discov. 2023;13:1922–47.
pubmed: 37191437
pmcid: 10401075
doi: 10.1158/2159-8290.CD-22-1396
Vujovic A, de Rooij L, Chahi AK, Chen HT, Yee BA, Loganathan SK, et al. In vivo screening unveils pervasive RNA-binding protein dependencies in leukemic stem cells and identifies ELAVL1 as a therapeutic target. Blood Cancer Discov. 2023;4:180–207.
pubmed: 36763002
pmcid: 10150294
doi: 10.1158/2643-3230.BCD-22-0086
Paczulla AM, Rothfelder K, Raffel S, Konantz M, Steinbacher J, Wang H, et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature. 2019;572:254–9.
pubmed: 31316209
pmcid: 6934414
doi: 10.1038/s41586-019-1410-1
Raffel S, Klimmeck D, Falcone M, Demir A, Pouya A, Zeisberger P, et al. Quantitative proteomics reveals specific metabolic features of acute myeloid leukemia stem cells. Blood. 2020;136:1507–19.
pubmed: 32556243
doi: 10.1182/blood.2019003654
Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41.
pubmed: 23333149
pmcid: 3595363
doi: 10.1016/j.stem.2012.12.013
van Galen P, Mbong N, Kreso A, Schoof EM, Wagenblast E, Ng SWK, et al. Integrated stress response activity marks stem cells in normal hematopoiesis and leukemia. Cell Rep. 2018;25:1109–17.e5.
pubmed: 30380403
doi: 10.1016/j.celrep.2018.10.021
Zeng A. BoneMarrowMap: A single cell RNA-seq reference map of human hematopoietic development in the bone marrow, with balanced representation of hematopoietic stem and progenitor cells and differentiated populations. Github https://github.com/andygxzeng/BoneMarrowMap (accessed 20 Dec2023).
Takayama N, Murison A, Takayanagi S-I, Arlidge C, Zhou S, Garcia-Prat L, et al. The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization. Cell Stem Cell. 2021;28:488–501.e10.
pubmed: 33242413
doi: 10.1016/j.stem.2020.11.001
Schwartz GW, Zhou Y, Petrovic J, Fasolino M, Xu L, Shaffer SM, et al. TooManyCells identifies and visualizes relationships of single-cell clades. Nat Methods. 2020;17:405–13.
pubmed: 32123397
pmcid: 7439807
doi: 10.1038/s41592-020-0748-5
Schwartz GW, Zhou Y, Petrovic J, Pear WS, Faryabi RB. TooManyPeaks identifies drug-resistant-specific regulatory elements from single-cell leukemic epigenomes. Cell Rep. 2021;36:109575.
pubmed: 34433064
pmcid: 8409102
doi: 10.1016/j.celrep.2021.109575
Itoh K, Tezuka H, Sakoda H, Konno M, Nagata K, Uchiyama T, et al. Reproducible establishment of hemopoietic supportive stromal cell lines from murine bone marrow. Exp Hematol. 1989;17:145–53.
pubmed: 2783573
Tirosh I, Izar B, Prakadan SM, Wadsworth MH, Treacy D, Trombetta JJ, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352:189–96.
pubmed: 27124452
pmcid: 4944528
doi: 10.1126/science.aad0501
O’Reilly E, Zeinabad HA, Szegezdi E. Hematopoietic versus leukemic stem cell quiescence: challenges and therapeutic opportunities. Blood Rev. 2021;50:100850.
pubmed: 34049731
doi: 10.1016/j.blre.2021.100850
Rehman SK, Haynes J, Collignon E, Brown KR, Wang Y, Nixon AML, et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell. 2021;184:226–42.e21.
pubmed: 33417860
doi: 10.1016/j.cell.2020.11.018
Li L, Fridley B, Kalari K, Jenkins G, Batzler A, Safgren S, et al. Gemcitabine and cytosine arabinoside cytotoxicity: association with lymphoblastoid cell expression. Cancer Res. 2008;68:7050–8.
pubmed: 18757419
pmcid: 2562356
doi: 10.1158/0008-5472.CAN-08-0405
Klco JM, Spencer DH, Miller CA, Griffith M, Lamprecht TL, O’Laughlin M, et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell. 2014;25:379–92.
pubmed: 24613412
pmcid: 3983786
doi: 10.1016/j.ccr.2014.01.031
Losman J-A, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C.et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339:1621–5.
Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl J Med. 2013;368:2059–74.
doi: 10.1056/NEJMoa1301689
Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010;17:13–27.
pubmed: 20060365
pmcid: 3008568
doi: 10.1016/j.ccr.2009.11.020
Boutzen H, Saland E, Larrue C, de Toni F, Gales L, Castelli FA, et al. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia. J Exp Med. 2016;213:483–97.
pubmed: 26951332
pmcid: 4821643
doi: 10.1084/jem.20150736
Epigenetic Therapies for Cancer | NEJM. https://www.nejm.org/doi/full/10.1056/NEJMra1805035?query=TOC .
Shih AH, Abdel-Wahab O, Patel JP, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer. 2012;12:599–612.
pubmed: 22898539
doi: 10.1038/nrc3343
Hua X, Zhao W, Pesatori AC, Consonni D, Caporaso NE, Zhang T, et al. Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma. Nat Commun. 2020;11:2459.
pubmed: 32424208
pmcid: 7235245
doi: 10.1038/s41467-020-16295-5
Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong W-J, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84.
pubmed: 25599133
pmcid: 4406275
doi: 10.1038/nm.3788
Tovy A, Reyes JM, Gundry MC, Brunetti L, Lee-Six H, Petljak M, et al. Tissue-biased expansion of DNMT3A-mutant clones in a mosaic individual is associated with conserved epigenetic erosion. Cell Stem Cell. 2020;27:326–35.e4.
pubmed: 32673568
pmcid: 7494054
doi: 10.1016/j.stem.2020.06.018
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67.
pubmed: 21130701
pmcid: 4105845
doi: 10.1016/j.ccr.2010.11.015