Molecules and Cells

  • 제46권10호
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  • Pages.611-626
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  • 2023
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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Identification of Cell Type-Specific Effects of DNMT3A Mutations on Relapse in Acute Myeloid Leukemia

  • Seo-Gyeong Bae (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Hyeoung-Joon Kim (Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University) ;
  • Mi Yeon Kim (Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University) ;
  • Dennis Dong Hwan Kim (Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto) ;
  • So-I Shin (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Jae-Sook Ahn (Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University) ;
  • Jihwan Park (School of Life Sciences, Gwangju Institute of Science and Technology (GIST))
  • 투고 : 2023.05.30
  • 심사 : 2023.08.01
  • 발행 : 2023.10.31
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초록

Acute myeloid leukemia (AML) is a heterogeneous disease caused by distinctive mutations in individual patients; therefore, each patient may display different cell-type compositions. Although most patients with AML achieve complete remission (CR) through intensive chemotherapy, the likelihood of relapse remains high. Several studies have attempted to characterize the genetic and cellular heterogeneity of AML; however, our understanding of the cellular heterogeneity of AML remains limited. In this study, we performed single-cell RNA sequencing (scRNAseq) of bone marrow-derived mononuclear cells obtained from same patients at different AML stages (diagnosis, CR, and relapse). We found that hematopoietic stem cells (HSCs) at diagnosis were abnormal compared to normal HSCs. By improving the detection of the DNMT3A R882 mutation with targeted scRNAseq, we identified that DNMT3A-mutant cells that mainly remained were granulocyte-monocyte progenitors (GMPs) or lymphoid-primed multipotential progenitors (LMPPs) from CR to relapse and that DNMT3A-mutant cells have gene signatures related to AML and leukemic cells. Copy number variation analysis at the single-cell level indicated that the cell type that possesses DNMT3A mutations is an important factor in AML relapse and that GMP and LMPP cells can affect relapse in patients with AML. This study advances our understanding of the role of DNMT3A in AML relapse and our approach can be applied to predict treatment outcomes.

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과제정보

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (NRF-2015R1A2A1A10054579) and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1720160), Chonnam National University Hwasun Hospital Institute for Biomedical Science (HCRI21006), an NRF grant funded by the Korean government (MSIT) (No. 2019R1C1C1005403, 2021M3H9A2097520, 2019R1A5A8083404, and 2018R1A2A1A05078480), and GIST-MIT Research Collaboration grant funded by the GIST.

참고문헌

  1. Addya, S., Keller, M.A., Delgrosso, K., Ponte, C.M., Vadigepalli, R., Gonye, G.E., and Surrey, S. (2004). Erythroid-induced commitment of K562 cells results in clusters of differentially expressed genes enriched for specific transcription regulatory elements. Physiol. Genomics 19, 117-130. https://doi.org/10.1152/physiolgenomics.00028.2004
  2. Ahn, J.S., Kim, H.J., Kim, Y.K., Lee, S.S., Ahn, S.Y., Jung, S.H., Yang, D.H., Lee, J.J., Park, H.J., Lee, J.Y., et al. (2018). Assessment of a new genomic classification system in acute myeloid leukemia with a normal karyotype. Oncotarget 9, 4961-4968. https://doi.org/10.18632/oncotarget.23575
  3. Aibar, S., Gonzalez-Blas, C.B., Moerman, T., Huynh-Thu, V.A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.C., Geurts, P., Aerts, J., et al. (2017). SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083-1086. https://doi.org/10.1038/nmeth.4463
  4. Alanazi, B., Munje, C.R., Rastogi, N., Williamson, A.J., Taylor, S., Hole, P.S., Hodges, M., Doyle, M., Baker, S., Gilkes, A.F., et al. (2020). Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia. Leukemia 34, 427-440. https://doi.org/10.1038/s41375-019-0596-4
  5. Arindrarto, W., Borras, D.M., de Groen, R.A., van den Berg, R.R., Locher, I.J., van Diessen, S.A., van der Holst, R., van der Meijden, E.D., Honders, M.W., de Leeuw, R.H., et al. (2021). Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing. Leukemia 35, 47-61. https://doi.org/10.1038/s41375-020-0762-8
  6. Bhatnagar, B., Eisfeld, A.K., Nicolet, D., Mrozek, K., Blachly, J.S., Orwick, S., Lucas, D.M., Kohlschmidt, J., Blum, W., Kolitz, J.E., et al. (2016). Persistence of DNMT 3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia. Br. J. Haematol. 175, 226-236. https://doi.org/10.1111/bjh.14254
  7. Buscarlet, M., Provost, S., Zada, Y.F., Barhdadi, A., Bourgoin, V., Lepine, G., Mollica, L., Szuber, N., Dube, M.P., and Busque, L. (2017). DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753-762. https://doi.org/10.1182/blood-2017-04-777029
  8. Cao, S., Wang, Z., Gao, X., He, W., Cai, Y., Chen, H., and Xu, R. (2018). FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC. J. Exp. Clin. Cancer Res. 37, 220.
  9. Challen, G.A., Sun, D., Jeong, M., Luo, M., Jelinek, J., Berg, J.S., Bock, C., Vasanthakumar, A., Gu, H., Xi, Y., et al. (2012). Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23-31. https://doi.org/10.1038/ng.1009
  10. Chapiro, E., Russell, L., Radford-Weiss, I., Bastard, C., Lessard, M., Struski, S., Cave, H., Fert-Ferrer, S., Barin, C., Maarek, O., et al. (2006). Overexpression of CEBPA resulting from the translocation t (14; 19)(q32; q13) of human precursor B acute lymphoblastic leukemia. Blood 108, 3560-3563. https://doi.org/10.1182/blood-2006-03-010835
  11. Chien, W., Sun, Q.Y., Ding, L.W., Mayakonda, A., Takao, S., Liu, L., Lim, S.L., Tan, K.T., Garg, M., De Sousa Maria Varela, A., et al. (2017). Diagnosis and relapse: cytogenetically normal acute myelogenous leukemia without FLT3-ITD or MLL-PTD. Leukemia 31, 762-766. https://doi.org/10.1038/leu.2016.343
  12. Choi, Y.H. and Kim, J.K. (2019). Dissecting cellular heterogeneity using single-cell RNA sequencing. Mol. Cells 42, 189-199.
  13. Chung, S.S., Eng, W.S., Hu, W., Khalaj, M., Garrett-Bakelman, F.E., Tavakkoli, M., Levine, R.L., Carroll, M., Klimek, V.M., Melnick, A.M., et al. (2017). CD99 is a therapeutic target on disease stem cells in myeloid malignancies. Sci. Transl. Med. 9, eaaj2025.
  14. Dillon, L.W., Ghannam, J., Nosiri, C., Gui, G., Goswami, M., Calvo, K.R., Lindblad, K.E., Oetjen, K.A., Wilkerson, M., Soltis, A.R., et al. (2021). Personalized single-cell proteogenomics to distinguish acute myeloid leukemia from non-malignant clonal hematopoiesis. Blood Cancer Discov. 2, 319-325. https://doi.org/10.1158/2643-3230.BCD-21-0046
  15. DiNardo, C.D. and Cortes, J.E. (2016). Mutations in AML: prognostic and therapeutic implications. Hematology Am. Soc. Hematol. Educ. Program 2016, 348-355. https://doi.org/10.1182/asheducation-2016.1.348
  16. Ediriwickrema, A., Aleshin, A., Reiter, J.G., Corces, M.R., Kohnke, T., Stafford, M., Liedtke, M., Medeiros, B.C., and Majeti, R. (2020). Single-cell mutational profiling enhances the clinical evaluation of AML MRD. Blood Adv. 4, 943-952. https://doi.org/10.1182/bloodadvances.2019001181
  17. Emperle, M., Adam, S., Kunert, S., Dukatz, M., Baude, A., Plass, C., Rathert, P., Bashtrykov, P., and Jeltsch, A. (2019). Mutations of R882 change flanking sequence preferences of the DNA methyltransferase DNMT3A and cellular methylation patterns. Nucleic Acids Res. 47, 11355-11367. https://doi.org/10.1093/nar/gkz911
  18. Eppert, K., Takenaka, K., Lechman, E.R., Waldron, L., Nilsson, B., Van Galen, P., Metzeler, K.H., Poeppl, A., Ling, V., Beyene, J., et al. (2011). Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 17, 1086-1093. https://doi.org/10.1038/nm.2415
  19. Erickson, A., He, M., Berglund, E., Marklund, M., Mirzazadeh, R., Schultz, N., Kvastad, L., Andersson, A., Bergenstrahle, L., Bergenstrahle, J., et al. (2022). Spatially resolved clonal copy number alterations in benign and malignant tissue. Nature 608, 360-367. https://doi.org/10.1038/s41586-022-05023-2
  20. Estey, E. and Dohner, H. (2006). Acute myeloid leukaemia. Lancet 368, 1894-1907. https://doi.org/10.1016/S0140-6736(06)69780-8
  21. Garg, M., Nagata, Y., Kanojia, D., Mayakonda, A., Yoshida, K., Haridas Keloth, S., Zang, Z.J., Okuno, Y., Shiraishi, Y., Chiba, K., et al. (2015). Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood 126, 2491-2501. https://doi.org/10.1182/blood-2015-05-646240
  22. Genovese, G., Kahler, A.K., Handsaker, R.E., Lindberg, J., Rose, S.A., Bakhoum, S.F., Chambert, K., Mick, E., Neale, B.M., Fromer, M., et al. (2014). Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477-2487. https://doi.org/10.1056/NEJMoa1409405
  23. Goardon, N., Marchi, E., Atzberger, A., Quek, L., Schuh, A., Soneji, S., Woll, P., Mead, A., Alford, K.A., Rout, R., et al. (2011). Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138-152. https://doi.org/10.1016/j.ccr.2010.12.012
  24. Han, B., Bhowmick, N., Qu, Y., Chung, S., Giuliano, A.E., and Cui, X. (2017). FOXC1: an emerging marker and therapeutic target for cancer. Oncogene 36, 3957-3963. https://doi.org/10.1038/onc.2017.48
  25. Handschuh, L., Kazmierczak, M., Milewski, M.C., Goralski, M., Luczak, M., Wojtaszewska, M., Uszczynska-Ratajczak, B., Lewandowski, K., Komarnicki, M., and Figlerowicz, M. (2018). Gene expression profiling of acute myeloid leukemia samples from adult patients with AML-M1 and-M2 through boutique microarrays, real-time PCR and droplet digital PCR. Int. J. Oncol. 52, 656-678.
  26. Heo, S.K., Noh, E.K., Ju, L.J., Sung, J.Y., Jeong, Y.K., Cheon, J., Koh, S.J., Min, Y.J., Choi, Y., and Jo, J.C. (2020). CD45 dim CD34+ CD38- CD133+ cells have the potential as leukemic stem cells in acute myeloid leukemia. BMC Cancer 20, 285.
  27. Huang, D.W., Sherman, B.T., and Lempicki, R.A. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44-57. https://doi.org/10.1038/nprot.2008.211
  28. Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P.V., Mar, B.G., Lindsley, R.C., Mermel, C.H., Burtt, N., Chavez, A., et al. (2014). Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488-2498. https://doi.org/10.1056/NEJMoa1408617
  29. Jan, M., Chao, M.P., Cha, A.C., Alizadeh, A.A., Gentles, A.J., Weissman, I.L., and Majeti, R. (2011). Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc. Natl. Acad. Sci. U. S. A. 108, 5009-5014. https://doi.org/10.1073/pnas.1100551108
  30. Jia, D., Jurkowska, R.Z., Zhang, X., Jeltsch, A., and Cheng, X. (2007). Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449, 248-251. https://doi.org/10.1038/nature06146
  31. Jongen-Lavrencic, M., Grob, T., Hanekamp, D., Kavelaars, F.G., Al Hinai, A., Zeilemaker, A., Erpelinck-Verschueren, C.A., Gradowska, P.L., Meijer, R., Cloos, J., et al. (2018). Molecular minimal residual disease in acute myeloid leukemia. N. Engl. J. Med. 378, 1189-1199. https://doi.org/10.1056/NEJMoa1716863
  32. Khwaja, A., Bjorkholm, M., Gale, R.E., Levine, R.L., Jordan, C.T., Ehninger, G., Bloomfield, C.D., Estey, E., Burnett, A., Cornelissen, J.J., et al. (2016). Acute myeloid leukaemia. Nat. Rev. Dis. Primers 2, 16010.
  33. Kuleshov, M.V., Jones, M.R., Rouillard, A.D., Fernandez, N.F., Duan, Q., Wang, Z., Koplev, S., Jenkins, S.L., Jagodnik, K.M., Lachmann, A., et al. (2016). Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44(W1), W90-W97. https://doi.org/10.1093/nar/gkw377
  34. Landberg, N., Hansen, N., Askmyr, M., Agerstam, H., Lassen, C., Rissler, M., Hjorth-Hansen, H., Mustjoki, S., Jaras, M., Richter, J., et al. (2016). IL1RAP expression as a measure of leukemic stem cell burden at diagnosis of chronic myeloid leukemia predicts therapy outcome. Leukemia 30, 255-258. https://doi.org/10.1038/leu.2015.135
  35. Ley, T.J., Miller, C., Ding, L., Raphael, B.J., Mungall, A.J., Robertson, A., Hoadley, K., Triche, T.J., Jr., Laird, P.W., Baty, J.D., et al. (2013). Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059-2074. https://doi.org/10.1056/NEJMoa1301689
  36. Li, K., Du, Y., Cai, Y., Liu, W., Lv, Y., Huang, B., Zhang, L., Wang, Z., Liu, P., Sun, Q., et al. (2023). Single-cell analysis reveals the chemotherapy-induced cellular reprogramming and novel therapeutic targets in relapsed/refractory acute myeloid leukemia. Leukemia 37, 308-325. https://doi.org/10.1038/s41375-022-01789-6
  37. Lin, T.C., Lee, C.Y., Tien, H.F., Hu, C.Y., Tang, J.L., and Lin, L.I. (2007). Tumor suppressor activity of CCAAT/enhancer binding protein alpha is epigenetically down-regulated in acute myeloid leukemia. Blood 110, 2113.
  38. Liu, W., Yi, J.M., Liu, Y., Chen, C., Zhang, K.X., Zhou, C., Zhan, H.E., Zhao, L., Morales, S., Zhao, X.L., et al. (2021). CDK6 is a potential prognostic biomarker in acute myeloid leukemia. Front. Genet. 11, 600227.
  39. Loghavi, S., Zuo, Z., Ravandi, F., Kantarjian, H.M., Bueso-Ramos, C., Zhang, L., Singh, R.R., Patel, K.P., Medeiros, L.J., Stingo, F., et al. (2014). Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations. J. Hematol. Oncol. 7, 74.
  40. Mayle, A., Yang, L., Rodriguez, B., Zhou, T., Chang, E., Curry, C.V., Challen, G.A., Li, W., Wheeler, D., Rebel, V.I., et al. (2015). Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood 125, 629-638. https://doi.org/10.1182/blood-2014-08-594648
  41. McKnight, S.L. (2001). McBindall-a better name for CCAAT/enhancer binding proteins? Cell 107, 259-261. https://doi.org/10.1016/S0092-8674(01)00543-8
  42. Meng, L., Liu, B., Ji, R., Jiang, X., Yan, X., and Xin, Y. (2019). Targeting the BDNF/TrkB pathway for the treatment of tumors. Oncol. Lett. 17, 2031-2039.
  43. Menter, D.G. and DuBois, R.N. (2012). Prostaglandins in cancer cell adhesion, migration, and invasion. Int. J. Cell Biol. 2012, 723419.
  44. Miles, L.A., Bowman, R.L., Merlinsky, T.R., Csete, I.S., Ooi, A.T., Durruthy-Durruthy, R., Bowman, M., Famulare, C., Patel, M.A., Mendez, P., et al. (2020). Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587, 477-482. https://doi.org/10.1038/s41586-020-2864-x
  45. Na, Y., Huang, G., and Wu, J. (2020). The role of RUNX1 in NF1-related tumors and blood disorders. Mol. Cells 43, 153-159.
  46. Okano, M., Bell, D.W., Haber, D.A., and Li, E. (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247-257. https://doi.org/10.1016/S0092-8674(00)81656-6
  47. Osorio, D., Zhong, Y., Li, G., Xu, Q., Yang, Y., Tian, Y., Chapkin, R.S., Huang, J.Z., and Cai, J.J. (2022). scTenifoldKnk: an efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation. Patterns (N. Y.) 3, 100434.
  48. Pabst, T. and Mueller, B.U. (2009). Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clin. Cancer Res. 15, 5303-5307. https://doi.org/10.1158/1078-0432.CCR-08-2941
  49. Paguirigan, A.L., Smith, J., Meshinchi, S., Carroll, M., Maley, C., and Radich, J.P. (2015). Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. Sci. Transl. Med. 7, 281re2.
  50. Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V.I., Paschka, P., Roberts, N.D., Potter, N.E., Heuser, M., Thol, F., Bolli, N., et al. (2016). Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374, 2209-2221. https://doi.org/10.1056/NEJMoa1516192
  51. Park, D.J., Kwon, A., Cho, B.S., Kim, H.J., Hwang, K.A., Kim, M., and Kim, Y. (2020). Characteristics of DNMT3A mutations in acute myeloid leukemia. Blood Res. 55, 17-26. https://doi.org/10.5045/br.2020.55.1.17
  52. Patel, A.P., Tirosh, I., Trombetta, J.J., Shalek, A.K., Gillespie, S.M., Wakimoto, H., Cahill, D.P., Nahed, B.V., Curry, W.T., Martuza, R.L., et al. (2014). Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396-1401. https://doi.org/10.1126/science.1254257
  53. Pellegrino, M., Sciambi, A., Treusch, S., Durruthy-Durruthy, R., Gokhale, K., Jacob, J., Chen, T.X., Geis, J.A., Oldham, W., Matthews, J., et al. (2018). High-throughput single-cell DNA sequencing of acute myeloid leukemia tumors with droplet microfluidics. Genome Res. 28, 1345-1352. https://doi.org/10.1101/gr.232272.117
  54. Petti, A.A., Williams, S.R., Miller, C.A., Fiddes, I.T., Srivatsan, S.N., Chen, D.Y., Fronick, C.C., Fulton, R.S., Church, D.M., and Ley, T.J. (2019). A general approach for detecting expressed mutations in AML cells using single cell RNA-sequencing. Nat. Commun. 10, 3660.
  55. Povinelli, B.J., Rodriguez-Meira, A., and Mead, A.J. (2018). Single cell analysis of normal and leukemic hematopoiesis. Mol. Aspects Med. 59, 85-94. https://doi.org/10.1016/j.mam.2017.08.006
  56. Radomska, H.S., Huettner, C.S., Zhang, P., Cheng, T., Scadden, D.T., and Tenen, D.G. (1998). CCAAT/enhancer binding protein α is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol. Cell. Biol. 18, 4301-4314. https://doi.org/10.1128/MCB.18.7.4301
  57. Russler-Germain, D.A., Spencer, D.H., Young, M.A., Lamprecht, T.L., Miller, C.A., Fulton, R., Meyer, M.R., Erdmann-Gilmore, P., Townsend, R.R., Wilson, R.K., et al. (2014). The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 25, 442-454. https://doi.org/10.1016/j.ccr.2014.02.010
  58. Sachs, K., Sarver, A.L., Noble-Orcutt, K.E., LaRue, R.S., Antony, M.L., Chang, D., Lee, Y., Navis, C.M., Hillesheim, A.L., Nykaza, I.R., et al. (2020). Single-cell gene expression analyses reveal distinct self-renewing and proliferating subsets in the leukemia stem cell compartment in acute myeloid leukemia. Cancer Res. 80, 458-470. https://doi.org/10.1158/0008-5472.CAN-18-2932
  59. Sauvageau, G., Thorsteinsdottir, U., Hough, M.R., Hugo, P., Lawrence, H.J., Largman, C., and Humphries, R.K. (1997). Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity 6, 13-22. https://doi.org/10.1016/S1074-7613(00)80238-1
  60. Schuurhuis, G.J., Meel, M.H., Wouters, F., Min, L.A., Terwijn, M., de Jonge, N.A., Kelder, A., Snel, A.N., Zweegman, S., Ossenkoppele, G.J., et al. (2013). Normal hematopoietic stem cells within the AML bone marrow have a distinct and higher ALDH activity level than co-existing leukemic stem cells. PLoS One 8, e78897.
  61. Scolnik, M.P., Morilla, R., de Bracco, M.M., Catovsky, D., and Matutes, E. (2002). CD34 and CD117 are overexpressed in AML and may be valuable to detect minimal residual disease. Leuk. Res. 26, 615-619. https://doi.org/10.1016/S0145-2126(01)00182-5
  62. Shlush, L.I., Mitchell, A., Heisler, L., Abelson, S., Ng, S.W., Trotman-Grant, A., Medeiros, J.J., Rao-Bhatia, A., Jaciw-Zurakowsky, I., Marke, R., et al. (2017). Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature 547, 104-108. https://doi.org/10.1038/nature22993
  63. Shlush, L.I., Zandi, S., Mitchell, A., Chen, W.C., Brandwein, J.M., Gupta, V., Kennedy, J.A., Schimmer, A.D., Schuh, A.C., Yee, K.W., et al. (2014). Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328-333. https://doi.org/10.1038/nature13038
  64. Stetson, L., Balasubramanian, D., Ribeiro, S.P., Stefan, T., Gupta, K., Xu, X., Fourati, S., Roe, A., Jackson, Z., Schauner, R., et al. (2021). Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression. Leukemia 35, 2799-2812. https://doi.org/10.1038/s41375-021-01338-7
  65. Thakral, D., Singh, V.K., Gupta, R., Jha, N., Khan, A., Kaur, G., Rai, S., Kumar, V., Supriya, M., Bakhshi, S., et al. (2023). Integrated single-cell transcriptome analysis of CD34+ enriched leukemic stem cells revealed intra-and inter-patient transcriptional heterogeneity in pediatric acute myeloid leukemia. Ann. Hematol. 102, 73-87. https://doi.org/10.1007/s00277-022-05021-4
  66. Trapnell, C., Cacchiarelli, D., Grimsby, J., Pokharel, P., Li, S., Morse, M., Lennon, N.J., Livak, K.J., Mikkelsen, T.S., and Rinn, J.L. (2014). The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381-386. https://doi.org/10.1038/nbt.2859
  67. Tyner, J.W., Tognon, C.E., Bottomly, D., Wilmot, B., Kurtz, S.E., Savage, S.L., Long, N., Schultz, A.R., Traer, E., Abel, M., et al. (2018). Functional genomic landscape of acute myeloid leukaemia. Nature 562, 526-531. https://doi.org/10.1038/s41586-018-0623-z
  68. van Galen, P., Hovestadt, V., Wadsworth, M.H., 2nd, Hughes, T.K., Griffin, G.K., Battaglia, S., Verga, J.A., Stephansky, J., Pastika, T.J., Story, J.L., et al. (2019). Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity. Cell 176, 1265-1281.e24. https://doi.org/10.1016/j.cell.2019.01.031
  69. Vosberg, S. and Greif, P.A. (2019). Clonal evolution of acute myeloid leukemia from diagnosis to relapse. Genes Chromosomes Cancer 58, 839-849. https://doi.org/10.1002/gcc.22806
  70. Wang, W., Stiehl, T., Raffel, S., Hoang, V.T., Hoffmann, I., Poisa-Beiro, L., Saeed, B.R., Blume, R., Manta, L., Eckstein, V., et al. (2017). Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia. Haematologica 102, 1567-1577. https://doi.org/10.3324/haematol.2016.163584
  71. Wesely, J., Kotini, A.G., Izzo, F., Luo, H., Yuan, H., Sun, J., Georgomanoli, M., Zviran, A., Deslauriers, A.G., Dusaj, N., et al. (2020). Acute myeloid leukemia iPSCs reveal a role for RUNX1 in the maintenance of human leukemia stem cells. Cell Rep. 31, 107688.
  72. Wu, Z., Huang, K., Yu, J., Le, T., Namihira, M., Liu, Y., Zhang, J., Xue, Z., Cheng, L., and Fan, G. (2012). Dnmt3a regulates both proliferation and differentiation of mouse neural stem cells. J. Neurosci. Res. 90, 1883-1891. https://doi.org/10.1002/jnr.23077
  73. Xu, J.l. and Guo, Y. (2020). FCGR1A serves as a novel biomarker and correlates with immune infiltration in four cancer types. Front. Mol. Biosci. 7, 581615.
  74. Yamashita, Y., Yuan, J., Suetake, I., Suzuki, H., Ishikawa, Y., Choi, Y., Ueno, T., Soda, M., Hamada, T., Haruta, H., et al. (2010). Array-based genomic resequencing of human leukemia. Oncogene 29, 3723-3731. https://doi.org/10.1038/onc.2010.117
  75. Yilmaz, M., Wang, F., Loghavi, S., Bueso-Ramos, C., Gumbs, C., Little, L., Song, X., Zhang, J., Kadia, T., Borthakur, G., et al. (2019). Late relapse in acute myeloid leukemia (AML): clonal evolution or therapy-related leukemia? Blood Cancer J. 9, 7.
  76. Yu, J., Li, Y., Zhang, D., Wan, D., and Jiang, Z. (2020). Clinical implications of recurrent gene mutations in acute myeloid leukemia. Exp. Hematol. Oncol. 9, 4.
  77. Yuan, X.Q., Peng, L., Zeng, W.J., Jiang, B.Y., Li, G.C., and Chen, X.P. (2016). DNMT3A R882 mutations predict a poor prognosis in AML: a meta-analysis from 4474 patients. Medicine (Baltimore) 95, e3519.
  78. Zhai, Y., Singh, P., Dolnik, A., Brazda, P., Atlasy, N., Del Gaudio, N., Dohner, K., Dohner, H., Minucci, S., Martens, J., et al. (2022). Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia. Mol. Cancer 21, 166.
  79. Zhang, P., Iwasaki-Arai, J., Iwasaki, H., Fenyus, M.L., Dayaram, T., Owens, B.M., Shigematsu, H., Levantini, E., Huettner, C.S., Lekstrom-Himes, J.A., et al. (2004). Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBPα. Immunity 21, 853-863. https://doi.org/10.1016/j.immuni.2004.11.006