Current Concepts of Leukemic Stem Cells: Origin, Characteristics, and its Clinical Implications in Acute Myeloid Leukemia
Main Article Content
Abstract
Despite significant advancements in therapy, patients diagnosed with acute myeloid leukemia (AML) continue to face poor outcomes, often experiencing relapses even after achieving initial complete remission. The occurrence of relapse is attributed to the inability of conventional treatment to eliminate a specific subset of cells within the bone marrow known as leukemic stem cells (LSCs). These specialized cells exhibit self-renewal capacity and have the ability to proliferate and differentiate into leukemic blasts. The accumulation of multiple genetic mutations in LSCs makes them resistant to standard chemotherapy. Several studies have been conducted to identify the phenotypic characteristics and genetic signatures of LSCs, with the aim of differentiating them from normal hematopoietic stem cells (HSCs). Understanding the role of LSCs in AML treatment resistance has paved the way for the development of targeted and more precise treatments, especially for relapsed AML patients, without affecting the healthy HSCs. This review elaborates on the origin, phenotypic and genotypic characteristics of LSCs, and their role in the biology of AML, with a brief note on therapies targeting LSCs.
Keywords:
acute myeloid leukemia, leukemic stem cells, immunophenotype, targeted therapy, relapsed AML
Article Details
How to Cite
SIVAKUMAR, Visaali; RAVI, Soundarya; MANIVANNAN, Prabhu.
Current Concepts of Leukemic Stem Cells: Origin, Characteristics, and its Clinical Implications in Acute Myeloid Leukemia.
Medical Research Archives, [S.l.], v. 12, n. 6, june 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5517>. Date accessed: 03 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i6.5517.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Bahl A, Sharma A, Raina V, et al. Long-term outcomes for patients with acute myeloid leukemia: a single-center experience from AIIMS, India. Asia Pac J Clin Oncol. 2015;11(3):242-252. Doi:10.1111/ajco.12333
2. Du M, Chen W, Liu K, et al. The Global Burden of Leukemia and Its Attributable Factors in 204 Countries and Territories: Findings from the Global Burden of Disease 2019 Study and Projections to 2030. J Oncol. 2022;2022:1612702. Published 2022 Apr 25. Doi:10.1155/2022/1612702
3. Zhang N, Wu J, Wang Q, et al. Global burden of hematologic malignancies and evolution patterns over the past 30 years. Blood Cancer J. 2023;13(1):82. Published 2023 May 17. Doi:10.1038/s41408-023-00853-3
4. Shimony S, Stahl M, Stone RM. Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(3):502-526. Doi:10.1002/ajh.26822
5. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. Doi:10.1038/s41375-022-01613-1
6. Wang X, Huang S, Chen JL. Understanding of leukemic stem cells and their clinical implications. Mol Cancer. 2017;16(1):2. Published 2017 Jan 30. Doi:10.1186/s12943-016-0574-7
7. Marchand T, Pinho S. Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities. Front Immunol. 2021;12:775128. Published 2021 Oct 15. Doi:10.3389/fimmu.2021.775128
8. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. Doi:10.1038/nm0797-730
9. Gianfaldoni G, Mannelli F, Baccini M, Antonioli E, Leoni F, Bosi A. Clearance of leukaemic blasts from peripheral blood during standard induction treatment predicts the bone marrow response in acute myeloid leukaemia: a pilot study. Br J Haematol. 2006;134(1):54-57. Doi:10.1111/j.1365-2141.2006.06100.x
10. Vergez F, Green AS, Tamburini J, et al. High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study. Haematologica. 2011;96(12):1792-1798. Doi:10.3324/haematol.2011.047894
11. Al-Mawali A, Gillis D, Lewis I. Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones. J Hematol Oncol. 2016;9(1):61. Published 2016 Jul 27. Doi:10.1186/s13045-016-0292-z
12. Roboz GJ, Guzman M. Acute myeloid leukemia stem cells: seek and destroy. Expert Rev Hematol. 2009;2(6):663-672. Doi:10.1586/ehm.09.53
13. Quek L, Otto GW, Garnett C, et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med. 2016;213(8):1513-1535. Doi:10.1084/jem.20151775
14. Chopra M, Bohlander SK. The cell of origin and the leukemia stem cell in acute myeloid leukemia. Genes Chromosomes Cancer. 2019;58(12):850-858. Doi:10.1002/gcc.22805
15. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4(1-2):7-25. PMID: 747780
16. Lord BI, Testa NG, Hendry JH. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood. 1975;46:65–72. (Lord BI, Testa NG, Hendry JH. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood. 1975;46(1):65-72. PMID: 1131427
17. Taichman RS, Reilly MJ, Emerson SG. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood. 1996;87(2):518-524. PMID: 8555473
18. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457-462. Published 2012 Jan 25. Doi:10.1038/nature10783
19. Kunisaki Y, Bruns I, Scheiermann C, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013;502(7473):637-643. Doi:10.1038/nature12612
20. Pinho S, Frenette PS. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol. 2019;20(5):303-320. Doi:10.1038/s41580-019-0103-9
21. Frenette PS, Pinho S, Lucas D, Scheiermann C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu Rev Immunol. 2013;31:285-316. Doi:10.1146/annurev-immunol-032712-095919
22. Méndez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829-834. Doi:10.1038/nature09262
23. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460(7252):259-263. Doi:10.1038/nature08099
24. Ye H, Adane B, Khan N, et al. Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche. Cell Stem Cell. 2016;19(1):23-37. Doi:10.1016/j.stem.2016.06.001
25. Boyd AL, Reid JC, Salci KR, et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol. 2017;19(11):1336-1347. Doi:10.1038/ncb3625
26. Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006;124(2):407-421. Doi:10.1016/j.cell.2005.10.041
27. Yamazaki S, Ema H, Karlsson G, et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147(5):1146-1158. Doi:10.1016/j.cell.2011.09.053
28. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645-648. Doi:10.1038/367645a0
29. Barreto IV, Pessoa FMCP, Machado CB, et al. Leukemic Stem Cell: A Mini-Review on Clinical Perspectives. Front Oncol. 2022;12:931050. Published 2022 Jun 24. Doi:10.3389/fonc.2022.931050
30. Jan M, Snyder TM, Corces-Zimmerman MR, et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med. 2012;4(149):149ra118. Doi:10.1126/scitranslmed.3004315
31. Wiseman DH, Greystoke BF, Somervaille TC. The variety of leukemic stem cells in myeloid malignancy. Oncogene. 2014;33(24):3091-3098. Doi:10.1038/onc.2013.269
32. Cancer Genome Atlas Research Network, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074. Doi:10.1056/NEJMoa1301689
33. Cheng WY, Li JF, Zhu YM, et al. Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia. Proc Natl Acad Sci U S A. 2022;119(49):e2211429119. Doi:10.1073/pnas.2211429119
34. Walcher L, Kistenmacher AK, Suo H, et al. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol. 2020;11:1280. Published 2020 Aug 7. Doi:10.3389/fimmu.2020.01280
35. Duarte D, Hawkins ED, Akinduro O, et al. Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML. Cell Stem Cell. 2018;22(1):64-77.e6. Doi:10.1016/j.stem.2017.11.006
36. Passaro D, Di Tullio A, Abarrategi A, et al. Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia. Cancer Cell. 2017;32(3):324-341.e6. Doi:10.1016/j.ccell.2017.08.001
37. Binder S, Luciano M, Horejs-Hoeck J. The cytokine network in acute myeloid leukemia (AML): A focus on pro- and anti-inflammatory mediators. Cytokine Growth Factor Rev. 2018;43:8-15. Doi:10.1016/j.cytogfr.2018.08.004
38. Ishikawa F, Yoshida S, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25(11):1315-1321. Doi:10.1038/nbt1350
39. Kumar B, Garcia M, Weng L, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia. 2018;32(3):575-587. Doi:10.1038/leu.2017.259
40. Lane SW, Wang YJ, Lo Celso C, et al. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood. 2011;118(10):2849-2856. Doi:10.1182/blood-2011-03-345165
41. Kampen KR, Ter Elst A, de Bont ES. Vascular endothelial growth factor signaling in acute myeloid leukemia. Cell Mol Life Sci. 2013;70(8):1307-1317. Doi:10.1007/s00018-012-1085-3
42. Forte D, García-Fernández M, Sánchez-Aguilera A, et al. Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy. Cell Metab. 2020;32(5):829-843.e9. Doi:10.1016/j.cmet.2020.09.001
43. Carter BZ, Mak PY, Chen Y, et al. Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network. Oncotarget. 2016;7(15):20054-20067. Doi:10.18632/oncotarget.7911
44. Zhou X, Zhou S, Li B, et al. Transmembrane TNF-α preferentially expressed by leukemia stem cells and blasts is a potent target for antibody therapy. Blood. 2015;126(12):1433-1442. Doi:10.1182/blood-2015-01-624833
45. Kagoya Y, Yoshimi A, Kataoka K, et al. Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. J Clin Invest. 2014;124(2):528-542. Doi:10.1172/JCI68101
46. Maryanovich M, Zahalka AH, Pierce H, et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche [published correction appears in Nat Med. 2019 Apr;25(4):701]. Nat Med. 2018;24(6):782-791. Doi:10.1038/s41591-018-0030-x
47. Taussig DC, Vargaftig J, Miraki-Moud F, et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood. 2010;115(10):1976-1984. Doi:10.1182/blood-2009-02-206565
48. Wunderlich M, Chou FS, Link KA, et al. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia. 2010;24(10):1785-1788. Doi:10.1038/leu.2010.158
49. Ito S, Barrett AJ, Dutra A, et al. Long term maintenance of myeloid leukemic stem cells cultured with unrelated human mesenchymal stromal cells. Stem Cell Res. 2015;14(1):95-104. Doi:10.1016/j.scr.2014.11.007
50. Zhi L, Wang M, Rao Q, Yu F, Mi Y, Wang J. Enrichment of N-Cadherin and Tie2-bearing CD34+/CD38-/CD123+ leukemic stem cells by chemotherapy-resistance. Cancer Lett. 2010;296(1):65-73. Doi:10.1016/j.canlet.2010.03.021
51. Qiu S, Jia Y, Xing H, et al. N-Cadherin and Tie2 positive CD34⁺CD38⁻CD123⁺ leukemic stem cell populations can develop acute myeloid leukemia more effectively in NOD/SCID mice. Leuk Res. 2014;38(5):632-637. Doi:10.1016/j.leukres.2014.03.007
52. Hosen N, Park CY, Tatsumi N, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci U S A. 2007;104(26):11008-11013. Doi:10.1073/pnas.0704271104
53. Pabst C, Bergeron A, Lavallée VP, et al. GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo. Blood. 2016;127(16):2018-2027. Doi:10.1182/blood-2015-11-683649
54. Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14(10):1777-1784. Doi:10.1038/sj.leu.2401903.
55. Hassanein NM, Alcancia F, Perkinson KR, Buckley PJ, Lagoo AS. Distinct expression patterns of CD123 and CD34 on normal bone marrow B-cell precursors ("hematogones") and B lymphoblastic leukemia blasts. Am J Clin Pathol. 2009;132(4):573-580. Doi:10.1309/AJCPO4DS0GTLSOEI
56. Bras AE, de Haas V, van Stigt A, et al. CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping. Cytometry B Clin Cytom. 2019;96(2):134-142. Doi:10.1002/cyto.b.21745
57. Mastelaro de Rezende M, Ferreira AT, Paredes-Gamero EJ. Leukemia stem cell immunophenotyping tool for diagnostic, prognosis, and therapeutics. J Cell Physiol. 2020;235(6):4989-4998. Doi:10.1002/jcp.29394
58. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377. Doi:10.1182/blood.2022016867
59. Cloos J, Harris JR, Janssen JJWM, et al. Comprehensive Protocol to Sample and Process Bone Marrow for Measuring Measurable Residual Disease and Leukemic Stem Cells in Acute Myeloid Leukemia. J Vis Exp. 2018;(133):56386. Published 2018 Mar 5. Doi:10.3791/56386
60. Kern W, Bacher U, Haferlach C, Schnittger S, Haferlach T. The role of multiparameter flow cytometry for disease monitoring in AML. Best Pract Res Clin Haematol. 2010;23(3):379-390. Doi:10.1016/j.beha.2010.06.007
61. Zeijlemaker W, Kelder A, Oussoren-Brockhoff YJ, et al. A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia. Leukemia. 2016;30(2):439-446. Doi:10.1038/leu.2015.252
62. Boscaro E, Urbino I, Catania FM, et al. Modern Risk Stratification of Acute Myeloid Leukemia in 2023: Integrating Established and Emerging Prognostic Factors. Cancers (Basel). 2023;15(13):3512. Published 2023 Jul 6. Doi:10.3390/cancers15133512
63. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021;138(26):2753-2767. Doi:10.1182/blood.2021013626
64. Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136-1152. Doi:10.1056/NEJMra1406184
65. Pravdic Z, Vukovic NS, Gasic V, et al. The influence of BCL2, BAX, and ABCB1 gene expression on prognosis of adult de novo acute myeloid leukemia with normal karyotype patients. Radiol Oncol. 2023;57(2):239-248. Published 2023 Apr 20. Doi:10.2478/raon-2023-0017
66. Marcucci G, Radmacher MD, Maharry K, et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1919-1928. Doi:10.1056/NEJMoa074256
67. Houthuijzen JM, Daenen LG, Roodhart JM, Voest EE. The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br J Cancer. 2012;106(12):1901-1906. Doi:10.1038/bjc.2012.201
68. O'Reilly E, Zeinabad HA, Szegezdi E. Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities. Blood Rev. 2021;50:100850. Doi:10.1016/j.blre.2021.100850
69. Witte KE, Ahlers J, Schäfer I, et al. High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia. Pediatr Hematol Oncol. 2011;28(2):91-99. Doi:10.3109/08880018.2010.528171
70. Kamel AM, Elsharkawy NM, Kandeel EZ, Hanafi M, Samra M, Osman RA. Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia. Front Oncol. 2022;12:867684. Published 2022 Apr 8. Doi:10.3389/fonc.2022.867684
71. van Rhenen A, Feller N, Kelder A, 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(18):6520-6527. Doi:10.1158/1078-0432.CCR-05-0468
72. Stelmach P, Trumpp A. Leukemic stem cells and therapy resistance in acute myeloid leukemia. Haematologica. 2023;108(2):353-366. Published 2023 Feb 1. Doi:10.3324/haematol.2022.280800
73. Lykon J, Madarang E, Nguyen N, Li W, Iyer SG, Stanchina M, et al. Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients. Blood 2021; 138 (Supplement 1): 4422. Doi: 10.1182/blood-2021-153143
74. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. Doi:10.1182/blood-2018-08-868752
75. Pabon CM, Abbas HA, Konopleva M. Acute myeloid leukemia: therapeutic targeting of stem cells. Expert Opin Ther Targets. 2022;26(6):547-556. Doi:10.1080/14728222.2022.2083957.
76. Kügler M, Stein C, Kellner C, et al. A recombinant trispecific single-chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting. Br J Haematol. 2010;150(5):574-586. Doi:10.1111/j.1365-2141.2010.08300.x
77. Pollard JA, Guest E, Alonzo TA, et al. Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric KMT2A-Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol. 2021;39(28):3149-3160. Doi:10.1200/JCO.20.03048.
78. He SZ, Busfield S, Ritchie DS, et al. A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk Lymphoma. 2015;56(5):1406-1415. Doi:10.3109/10428194.2014.956316
79. Kubasch AS, Schulze F, Giagounidis A, et al. Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. Leukemia. 2020;34(4):1182-1186. Doi:10.1038/s41375-019-0645-z
80. Deshpande AJ, Cusan M, Rawat VP, et al. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell. 2006;10(5):363-374. Doi:10.1016/j.ccr.2006.08.023
81. van Rhenen A, Moshaver B, Kelder A, et al. Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia. 2007;21(8):1700-1707. Doi:10.1038/sj.leu.2404754
82. Bonardi F, Fusetti F, Deelen P, van Gosliga D, Vellenga E, Schuringa JJ. A proteomics and transcriptomics approach to identify leukemic stem cell (LSC) markers. Mol Cell Proteomics. 2013;12(3):626-637. Doi:10.1074/mcp.M112.021931
83. Garg S, Shanmukhaiah C, Marathe S, et al. Differential antigen expression and aberrant signaling via PI3/AKT, MAP/ERK, JAK/STAT, and Wnt/β catenin pathways in Lin-/CD38-/CD34+ cells in acute myeloid leukemia. Eur J Haematol. 2016;96(3):309-317. Doi:10.1111/ejh.12592
84. Yabushita T, Satake H, Maruoka H, et al. Expression of multiple leukemic stem cell markers is associated with poor prognosis in de novo acute myeloid leukemia. Leuk Lymphoma. 2018;59(9):2144-2151. Doi:10.1080/10428194.2017.1410888
85. Goldenson BH, Goodman AM, Ball ED. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia in adults. Expert Opin Biol Ther. 2021;21(7):849-862. Doi:10.1080/14712598.2021.1825678
86. Abedin S, Guru Murthy GS, Szabo A, Hamadani M, Michaelis LC, Carlson KS, et al. Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features. Blood. 2022;140(Supplement 1):157–8. Doi:10.1182/blood-2022-157827
87. Stein EM, Walter RB, Erba HP, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood. 2018;131(4):387-396. Doi:10.1182/blood-2017-06-789800
88. Ravandi F, Walter RB, Subklewe M, Buecklein V, Jongen-Lavrencic M, Paschka P, et al. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML). JCO. 2020;38:7508–7508. Doi:10.1200/JCO.2020.38.15_suppl.7508
89. Shah NN, Tasian SK, Kohler ME, Hsieh EM, Baumeister SHC, Summers C, et al. CD33 CAR T-Cells (CD33CART) for Children and Young Adults with Relapsed/Refractory AML: Dose-Escalation Results from a Phase I/II Multicenter Trial. Blood. 2023;142:771. Doi:10.1182/blood-2023-179667
90. Montesinos P, Roboz GJ, Bulabois CE, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia. 2021;35(1):62-74. Doi:10.1038/s41375-020-0773-5
91. Daver NG, Montesinos P, DeAngelo DJ, Wang ES, Todisco E, Tarella C, et al. A phase I/II study of IMGN632, a novel CD123-targeting antibody-drug conjugate, in patients with relapsed/refractory acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, and other CD123-positive hematologic malignancies. JCO. 2020;38:TPS7563–TPS7563. Doi:10.1200/JCO.2020.38.15_suppl.TPS7563
92. Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137(6):751-762. Doi:10.1182/blood.2020007732
93. Gramatzki M, Staudinger M, Kellner C, Bulduk M, Schub N, Humpe A, et al. CD96 Antibody TH-111 Eradicates AML-LSC from Autografts and the Fc- Engineered Variant MSH-TH111e May be Used In Vivo. Biology of Blood and Marrow Transplantation. 2016;22:S200. Doi:10.1016/j.bbmt.2015.11.590
94. Brunner AM, Esteve J, Porkka K, et al. Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM-3 antibody, in combination with decitabine or azacitidine in high- or very high-risk myelodysplastic syndromes. Am J Hematol. 2024;99(2):E32-E36. Doi:10.1002/ajh.27161
95. Jin X, Zhang M, Sun R, et al. First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia. J Hematol Oncol. 2022;15(1):88. Published 2022 Jul 7. Doi:10.1186/s13045-022-01308-1
96. Wilde L, Martinez-Outschoorn U, Palmisiano N, Kasner M. OPB-111077 in Combination with Decitabine and Venetoclax for the Treatment of Acute Myeloid Leukemia. Blood. 2019;134:2597. Doi: 10.1182/blood-2019-131979
97. Ji Q, Ding YH, Sun Y, et al. Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells. Oncotarget. 2016;7(40):65012-65023. Doi:10.18632/oncotarget.11342
98. Lee JH, Faderl S, Pagel JM, et al. Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. Blood Adv. 2020;4(9):2032-2043. Doi:10.1182/bloodadvances.2019000757
99. Uy GL, Rettig MP, Stone RM, et al. A phase 1/2 study of chemosensitization with plerixafor plus G-CSF in relapsed or refractory acute myeloid leukemia. Blood Cancer J. 2017;7(3):e542. Published 2017 Mar 10. Doi:10.1038/bcj.2017.21
2. Du M, Chen W, Liu K, et al. The Global Burden of Leukemia and Its Attributable Factors in 204 Countries and Territories: Findings from the Global Burden of Disease 2019 Study and Projections to 2030. J Oncol. 2022;2022:1612702. Published 2022 Apr 25. Doi:10.1155/2022/1612702
3. Zhang N, Wu J, Wang Q, et al. Global burden of hematologic malignancies and evolution patterns over the past 30 years. Blood Cancer J. 2023;13(1):82. Published 2023 May 17. Doi:10.1038/s41408-023-00853-3
4. Shimony S, Stahl M, Stone RM. Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(3):502-526. Doi:10.1002/ajh.26822
5. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. Doi:10.1038/s41375-022-01613-1
6. Wang X, Huang S, Chen JL. Understanding of leukemic stem cells and their clinical implications. Mol Cancer. 2017;16(1):2. Published 2017 Jan 30. Doi:10.1186/s12943-016-0574-7
7. Marchand T, Pinho S. Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities. Front Immunol. 2021;12:775128. Published 2021 Oct 15. Doi:10.3389/fimmu.2021.775128
8. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. Doi:10.1038/nm0797-730
9. Gianfaldoni G, Mannelli F, Baccini M, Antonioli E, Leoni F, Bosi A. Clearance of leukaemic blasts from peripheral blood during standard induction treatment predicts the bone marrow response in acute myeloid leukaemia: a pilot study. Br J Haematol. 2006;134(1):54-57. Doi:10.1111/j.1365-2141.2006.06100.x
10. Vergez F, Green AS, Tamburini J, et al. High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study. Haematologica. 2011;96(12):1792-1798. Doi:10.3324/haematol.2011.047894
11. Al-Mawali A, Gillis D, Lewis I. Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones. J Hematol Oncol. 2016;9(1):61. Published 2016 Jul 27. Doi:10.1186/s13045-016-0292-z
12. Roboz GJ, Guzman M. Acute myeloid leukemia stem cells: seek and destroy. Expert Rev Hematol. 2009;2(6):663-672. Doi:10.1586/ehm.09.53
13. Quek L, Otto GW, Garnett C, et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med. 2016;213(8):1513-1535. Doi:10.1084/jem.20151775
14. Chopra M, Bohlander SK. The cell of origin and the leukemia stem cell in acute myeloid leukemia. Genes Chromosomes Cancer. 2019;58(12):850-858. Doi:10.1002/gcc.22805
15. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4(1-2):7-25. PMID: 747780
16. Lord BI, Testa NG, Hendry JH. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood. 1975;46:65–72. (Lord BI, Testa NG, Hendry JH. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood. 1975;46(1):65-72. PMID: 1131427
17. Taichman RS, Reilly MJ, Emerson SG. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood. 1996;87(2):518-524. PMID: 8555473
18. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457-462. Published 2012 Jan 25. Doi:10.1038/nature10783
19. Kunisaki Y, Bruns I, Scheiermann C, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013;502(7473):637-643. Doi:10.1038/nature12612
20. Pinho S, Frenette PS. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol. 2019;20(5):303-320. Doi:10.1038/s41580-019-0103-9
21. Frenette PS, Pinho S, Lucas D, Scheiermann C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu Rev Immunol. 2013;31:285-316. Doi:10.1146/annurev-immunol-032712-095919
22. Méndez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829-834. Doi:10.1038/nature09262
23. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460(7252):259-263. Doi:10.1038/nature08099
24. Ye H, Adane B, Khan N, et al. Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche. Cell Stem Cell. 2016;19(1):23-37. Doi:10.1016/j.stem.2016.06.001
25. Boyd AL, Reid JC, Salci KR, et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol. 2017;19(11):1336-1347. Doi:10.1038/ncb3625
26. Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006;124(2):407-421. Doi:10.1016/j.cell.2005.10.041
27. Yamazaki S, Ema H, Karlsson G, et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147(5):1146-1158. Doi:10.1016/j.cell.2011.09.053
28. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645-648. Doi:10.1038/367645a0
29. Barreto IV, Pessoa FMCP, Machado CB, et al. Leukemic Stem Cell: A Mini-Review on Clinical Perspectives. Front Oncol. 2022;12:931050. Published 2022 Jun 24. Doi:10.3389/fonc.2022.931050
30. Jan M, Snyder TM, Corces-Zimmerman MR, et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med. 2012;4(149):149ra118. Doi:10.1126/scitranslmed.3004315
31. Wiseman DH, Greystoke BF, Somervaille TC. The variety of leukemic stem cells in myeloid malignancy. Oncogene. 2014;33(24):3091-3098. Doi:10.1038/onc.2013.269
32. Cancer Genome Atlas Research Network, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074. Doi:10.1056/NEJMoa1301689
33. Cheng WY, Li JF, Zhu YM, et al. Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia. Proc Natl Acad Sci U S A. 2022;119(49):e2211429119. Doi:10.1073/pnas.2211429119
34. Walcher L, Kistenmacher AK, Suo H, et al. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol. 2020;11:1280. Published 2020 Aug 7. Doi:10.3389/fimmu.2020.01280
35. Duarte D, Hawkins ED, Akinduro O, et al. Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML. Cell Stem Cell. 2018;22(1):64-77.e6. Doi:10.1016/j.stem.2017.11.006
36. Passaro D, Di Tullio A, Abarrategi A, et al. Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia. Cancer Cell. 2017;32(3):324-341.e6. Doi:10.1016/j.ccell.2017.08.001
37. Binder S, Luciano M, Horejs-Hoeck J. The cytokine network in acute myeloid leukemia (AML): A focus on pro- and anti-inflammatory mediators. Cytokine Growth Factor Rev. 2018;43:8-15. Doi:10.1016/j.cytogfr.2018.08.004
38. Ishikawa F, Yoshida S, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25(11):1315-1321. Doi:10.1038/nbt1350
39. Kumar B, Garcia M, Weng L, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia. 2018;32(3):575-587. Doi:10.1038/leu.2017.259
40. Lane SW, Wang YJ, Lo Celso C, et al. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood. 2011;118(10):2849-2856. Doi:10.1182/blood-2011-03-345165
41. Kampen KR, Ter Elst A, de Bont ES. Vascular endothelial growth factor signaling in acute myeloid leukemia. Cell Mol Life Sci. 2013;70(8):1307-1317. Doi:10.1007/s00018-012-1085-3
42. Forte D, García-Fernández M, Sánchez-Aguilera A, et al. Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy. Cell Metab. 2020;32(5):829-843.e9. Doi:10.1016/j.cmet.2020.09.001
43. Carter BZ, Mak PY, Chen Y, et al. Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network. Oncotarget. 2016;7(15):20054-20067. Doi:10.18632/oncotarget.7911
44. Zhou X, Zhou S, Li B, et al. Transmembrane TNF-α preferentially expressed by leukemia stem cells and blasts is a potent target for antibody therapy. Blood. 2015;126(12):1433-1442. Doi:10.1182/blood-2015-01-624833
45. Kagoya Y, Yoshimi A, Kataoka K, et al. Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. J Clin Invest. 2014;124(2):528-542. Doi:10.1172/JCI68101
46. Maryanovich M, Zahalka AH, Pierce H, et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche [published correction appears in Nat Med. 2019 Apr;25(4):701]. Nat Med. 2018;24(6):782-791. Doi:10.1038/s41591-018-0030-x
47. Taussig DC, Vargaftig J, Miraki-Moud F, et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood. 2010;115(10):1976-1984. Doi:10.1182/blood-2009-02-206565
48. Wunderlich M, Chou FS, Link KA, et al. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia. 2010;24(10):1785-1788. Doi:10.1038/leu.2010.158
49. Ito S, Barrett AJ, Dutra A, et al. Long term maintenance of myeloid leukemic stem cells cultured with unrelated human mesenchymal stromal cells. Stem Cell Res. 2015;14(1):95-104. Doi:10.1016/j.scr.2014.11.007
50. Zhi L, Wang M, Rao Q, Yu F, Mi Y, Wang J. Enrichment of N-Cadherin and Tie2-bearing CD34+/CD38-/CD123+ leukemic stem cells by chemotherapy-resistance. Cancer Lett. 2010;296(1):65-73. Doi:10.1016/j.canlet.2010.03.021
51. Qiu S, Jia Y, Xing H, et al. N-Cadherin and Tie2 positive CD34⁺CD38⁻CD123⁺ leukemic stem cell populations can develop acute myeloid leukemia more effectively in NOD/SCID mice. Leuk Res. 2014;38(5):632-637. Doi:10.1016/j.leukres.2014.03.007
52. Hosen N, Park CY, Tatsumi N, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci U S A. 2007;104(26):11008-11013. Doi:10.1073/pnas.0704271104
53. Pabst C, Bergeron A, Lavallée VP, et al. GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo. Blood. 2016;127(16):2018-2027. Doi:10.1182/blood-2015-11-683649
54. Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14(10):1777-1784. Doi:10.1038/sj.leu.2401903.
55. Hassanein NM, Alcancia F, Perkinson KR, Buckley PJ, Lagoo AS. Distinct expression patterns of CD123 and CD34 on normal bone marrow B-cell precursors ("hematogones") and B lymphoblastic leukemia blasts. Am J Clin Pathol. 2009;132(4):573-580. Doi:10.1309/AJCPO4DS0GTLSOEI
56. Bras AE, de Haas V, van Stigt A, et al. CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping. Cytometry B Clin Cytom. 2019;96(2):134-142. Doi:10.1002/cyto.b.21745
57. Mastelaro de Rezende M, Ferreira AT, Paredes-Gamero EJ. Leukemia stem cell immunophenotyping tool for diagnostic, prognosis, and therapeutics. J Cell Physiol. 2020;235(6):4989-4998. Doi:10.1002/jcp.29394
58. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377. Doi:10.1182/blood.2022016867
59. Cloos J, Harris JR, Janssen JJWM, et al. Comprehensive Protocol to Sample and Process Bone Marrow for Measuring Measurable Residual Disease and Leukemic Stem Cells in Acute Myeloid Leukemia. J Vis Exp. 2018;(133):56386. Published 2018 Mar 5. Doi:10.3791/56386
60. Kern W, Bacher U, Haferlach C, Schnittger S, Haferlach T. The role of multiparameter flow cytometry for disease monitoring in AML. Best Pract Res Clin Haematol. 2010;23(3):379-390. Doi:10.1016/j.beha.2010.06.007
61. Zeijlemaker W, Kelder A, Oussoren-Brockhoff YJ, et al. A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia. Leukemia. 2016;30(2):439-446. Doi:10.1038/leu.2015.252
62. Boscaro E, Urbino I, Catania FM, et al. Modern Risk Stratification of Acute Myeloid Leukemia in 2023: Integrating Established and Emerging Prognostic Factors. Cancers (Basel). 2023;15(13):3512. Published 2023 Jul 6. Doi:10.3390/cancers15133512
63. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021;138(26):2753-2767. Doi:10.1182/blood.2021013626
64. Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136-1152. Doi:10.1056/NEJMra1406184
65. Pravdic Z, Vukovic NS, Gasic V, et al. The influence of BCL2, BAX, and ABCB1 gene expression on prognosis of adult de novo acute myeloid leukemia with normal karyotype patients. Radiol Oncol. 2023;57(2):239-248. Published 2023 Apr 20. Doi:10.2478/raon-2023-0017
66. Marcucci G, Radmacher MD, Maharry K, et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1919-1928. Doi:10.1056/NEJMoa074256
67. Houthuijzen JM, Daenen LG, Roodhart JM, Voest EE. The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br J Cancer. 2012;106(12):1901-1906. Doi:10.1038/bjc.2012.201
68. O'Reilly E, Zeinabad HA, Szegezdi E. Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities. Blood Rev. 2021;50:100850. Doi:10.1016/j.blre.2021.100850
69. Witte KE, Ahlers J, Schäfer I, et al. High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia. Pediatr Hematol Oncol. 2011;28(2):91-99. Doi:10.3109/08880018.2010.528171
70. Kamel AM, Elsharkawy NM, Kandeel EZ, Hanafi M, Samra M, Osman RA. Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia. Front Oncol. 2022;12:867684. Published 2022 Apr 8. Doi:10.3389/fonc.2022.867684
71. van Rhenen A, Feller N, Kelder A, 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(18):6520-6527. Doi:10.1158/1078-0432.CCR-05-0468
72. Stelmach P, Trumpp A. Leukemic stem cells and therapy resistance in acute myeloid leukemia. Haematologica. 2023;108(2):353-366. Published 2023 Feb 1. Doi:10.3324/haematol.2022.280800
73. Lykon J, Madarang E, Nguyen N, Li W, Iyer SG, Stanchina M, et al. Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients. Blood 2021; 138 (Supplement 1): 4422. Doi: 10.1182/blood-2021-153143
74. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. Doi:10.1182/blood-2018-08-868752
75. Pabon CM, Abbas HA, Konopleva M. Acute myeloid leukemia: therapeutic targeting of stem cells. Expert Opin Ther Targets. 2022;26(6):547-556. Doi:10.1080/14728222.2022.2083957.
76. Kügler M, Stein C, Kellner C, et al. A recombinant trispecific single-chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting. Br J Haematol. 2010;150(5):574-586. Doi:10.1111/j.1365-2141.2010.08300.x
77. Pollard JA, Guest E, Alonzo TA, et al. Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric KMT2A-Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol. 2021;39(28):3149-3160. Doi:10.1200/JCO.20.03048.
78. He SZ, Busfield S, Ritchie DS, et al. A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk Lymphoma. 2015;56(5):1406-1415. Doi:10.3109/10428194.2014.956316
79. Kubasch AS, Schulze F, Giagounidis A, et al. Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. Leukemia. 2020;34(4):1182-1186. Doi:10.1038/s41375-019-0645-z
80. Deshpande AJ, Cusan M, Rawat VP, et al. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell. 2006;10(5):363-374. Doi:10.1016/j.ccr.2006.08.023
81. van Rhenen A, Moshaver B, Kelder A, et al. Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia. 2007;21(8):1700-1707. Doi:10.1038/sj.leu.2404754
82. Bonardi F, Fusetti F, Deelen P, van Gosliga D, Vellenga E, Schuringa JJ. A proteomics and transcriptomics approach to identify leukemic stem cell (LSC) markers. Mol Cell Proteomics. 2013;12(3):626-637. Doi:10.1074/mcp.M112.021931
83. Garg S, Shanmukhaiah C, Marathe S, et al. Differential antigen expression and aberrant signaling via PI3/AKT, MAP/ERK, JAK/STAT, and Wnt/β catenin pathways in Lin-/CD38-/CD34+ cells in acute myeloid leukemia. Eur J Haematol. 2016;96(3):309-317. Doi:10.1111/ejh.12592
84. Yabushita T, Satake H, Maruoka H, et al. Expression of multiple leukemic stem cell markers is associated with poor prognosis in de novo acute myeloid leukemia. Leuk Lymphoma. 2018;59(9):2144-2151. Doi:10.1080/10428194.2017.1410888
85. Goldenson BH, Goodman AM, Ball ED. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia in adults. Expert Opin Biol Ther. 2021;21(7):849-862. Doi:10.1080/14712598.2021.1825678
86. Abedin S, Guru Murthy GS, Szabo A, Hamadani M, Michaelis LC, Carlson KS, et al. Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features. Blood. 2022;140(Supplement 1):157–8. Doi:10.1182/blood-2022-157827
87. Stein EM, Walter RB, Erba HP, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood. 2018;131(4):387-396. Doi:10.1182/blood-2017-06-789800
88. Ravandi F, Walter RB, Subklewe M, Buecklein V, Jongen-Lavrencic M, Paschka P, et al. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML). JCO. 2020;38:7508–7508. Doi:10.1200/JCO.2020.38.15_suppl.7508
89. Shah NN, Tasian SK, Kohler ME, Hsieh EM, Baumeister SHC, Summers C, et al. CD33 CAR T-Cells (CD33CART) for Children and Young Adults with Relapsed/Refractory AML: Dose-Escalation Results from a Phase I/II Multicenter Trial. Blood. 2023;142:771. Doi:10.1182/blood-2023-179667
90. Montesinos P, Roboz GJ, Bulabois CE, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia. 2021;35(1):62-74. Doi:10.1038/s41375-020-0773-5
91. Daver NG, Montesinos P, DeAngelo DJ, Wang ES, Todisco E, Tarella C, et al. A phase I/II study of IMGN632, a novel CD123-targeting antibody-drug conjugate, in patients with relapsed/refractory acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, and other CD123-positive hematologic malignancies. JCO. 2020;38:TPS7563–TPS7563. Doi:10.1200/JCO.2020.38.15_suppl.TPS7563
92. Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137(6):751-762. Doi:10.1182/blood.2020007732
93. Gramatzki M, Staudinger M, Kellner C, Bulduk M, Schub N, Humpe A, et al. CD96 Antibody TH-111 Eradicates AML-LSC from Autografts and the Fc- Engineered Variant MSH-TH111e May be Used In Vivo. Biology of Blood and Marrow Transplantation. 2016;22:S200. Doi:10.1016/j.bbmt.2015.11.590
94. Brunner AM, Esteve J, Porkka K, et al. Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM-3 antibody, in combination with decitabine or azacitidine in high- or very high-risk myelodysplastic syndromes. Am J Hematol. 2024;99(2):E32-E36. Doi:10.1002/ajh.27161
95. Jin X, Zhang M, Sun R, et al. First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia. J Hematol Oncol. 2022;15(1):88. Published 2022 Jul 7. Doi:10.1186/s13045-022-01308-1
96. Wilde L, Martinez-Outschoorn U, Palmisiano N, Kasner M. OPB-111077 in Combination with Decitabine and Venetoclax for the Treatment of Acute Myeloid Leukemia. Blood. 2019;134:2597. Doi: 10.1182/blood-2019-131979
97. Ji Q, Ding YH, Sun Y, et al. Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells. Oncotarget. 2016;7(40):65012-65023. Doi:10.18632/oncotarget.11342
98. Lee JH, Faderl S, Pagel JM, et al. Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. Blood Adv. 2020;4(9):2032-2043. Doi:10.1182/bloodadvances.2019000757
99. Uy GL, Rettig MP, Stone RM, et al. A phase 1/2 study of chemosensitization with plerixafor plus G-CSF in relapsed or refractory acute myeloid leukemia. Blood Cancer J. 2017;7(3):e542. Published 2017 Mar 10. Doi:10.1038/bcj.2017.21