Advertisement

Acute Myeloid Leukemia Stem Cell Heterogeneity and Its Clinical Relevance

  • Theodoros Karantanos
  • Richard J. JonesEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1139)

Abstract

The failure of complete remissions to reliably translate into cures in acute myeloid leukemia (AML) can be explained by the leukemia stem cell (LSC) paradigm, which hypothesizes that rare leukemia cells with stem cell features, including self-renewal capacity and drug resistance, are primarily responsible for both disease maintenance and relapses. Traditionally, the ability to generate AML in immunocompromised mice were how these so-called LSCs were identified. Only those rare AML cells characterized by a hematopoietic stem cell (HSC) CD34+CD38 phenotype were believed capable of generating leukemia in immunocompromised mice, but more recently, significant heterogeneity in the phenotypes of engrafting AML cells has been demonstrated. Moreover, AML cells that engraft immunocompromised mice do not necessarily represent either the founder clone or those cells responsible for relapse. A recent study found that the most immature phenotype present in an AML was heterogeneous, but correlated with genetically defined risk groups and outcomes. Patients with AML cells expressing a primitive HSC phenotype (CD34+CD38 with high aldehyde dehydrogenase activity) manifested significantly lower complete remission rates, as well as poorer event-free and overall survivals. AMLs in which the most primitive cells displayed more mature phenotypes were associated with better outcomes. The strong clinical correlations suggest that the most immature phenotype detectable within a patient’s AML might serve as a biomarker for “clinically relevant” LSCs. The minimal residual disease state during first remission may be the optimal setting to study novel LSC-targeted therapies, since they may have limited activity against the bulk leukemia and will be utilized at lowest tumor burden as well as least tumor heterogeneity.

Keywords

Acute myeloid leukemia Leukemia stem cells Heterogeneity CD34 CD38 Aldehyde dehydrogenase CD33 CD123 CLL-1 

References

  1. Ailles LE, Gerhard B, Hogge DE (1997) Detection and characterization of primitive malignant and normal progenitors in patients with acute myelogenous leukemia using long-term coculture with supportive feeder layers and cytokines. Blood 90(7):2555–2564PubMedPubMedCentralGoogle Scholar
  2. Al-Hussaini M, Rettig MP, Ritchey JK, Karpova D, Uy GL, Eissenberg LG et al (2016) Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 127(1):122–131PubMedPubMedCentralCrossRefGoogle Scholar
  3. Al-Mawali A, Gillis D, Lewis I (2016) Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones. J Hematol Oncol 9(1):61PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA et al (2004) C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res 64(22):8443–8450PubMedCrossRefPubMedCentralGoogle Scholar
  5. Bista R, Lee DW, Pepper OB, Azorsa DO, Arceci RJ, Aleem E (2017) Disulfiram overcomes bortezomib and cytarabine resistance in Down-syndrome-associated acute myeloid leukemia cells. J Exp Clin Cancer Res 36(1):22PubMedPubMedCentralCrossRefGoogle Scholar
  6. Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ (1997) Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 89(9):3104–3112PubMedPubMedCentralGoogle Scholar
  7. Bonifant CL, Szoor A, Torres D, Joseph N, Velasquez MP, Iwahori K et al (2016) CD123-engager T cells as a novel immunotherapeutic for Acute Myeloid Leukemia. Mol Ther J Am Soc Gene Ther 24(9):1615–1626CrossRefGoogle Scholar
  8. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bouchlaka MN, Redelman D, Murphy WJ (2010) Immunotherapy following hematopoietic stem cell transplantation: potential for synergistic effects. Immunotherapy 2(3):399–418PubMedPubMedCentralCrossRefGoogle Scholar
  10. Burnett AK, Mohite U (2006) Treatment of older patients with acute myeloid leukemia--new agents. Semin Hematol 43(2):96–106PubMedCrossRefPubMedCentralGoogle Scholar
  11. Cheung AM, Wan TS, Leung JC, Chan LY, Huang H, Kwong YL et al (2007) Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential. Leukemia 21(7):1423–1430PubMedCrossRefPubMedCentralGoogle Scholar
  12. Chichili GR, Huang L, Li H, Burke S, He L, Tang Q et al (2015) A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. Sci Transl Med 7(289):289ra82PubMedCrossRefPubMedCentralGoogle Scholar
  13. Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ et al (2006) Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A 103(31):11707–11712PubMedPubMedCentralCrossRefGoogle Scholar
  14. Conticello C, Martinetti D, Adamo L, Buccheri S, Giuffrida R, Parrinello N et al (2012) Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies. Int J Cancer 131(9):2197–2203PubMedCrossRefPubMedCentralGoogle Scholar
  15. Dao MA, Arevalo J, Nolta JA (2003) Reversibility of CD34 expression on human hematopoietic stem cells that retain the capacity for secondary reconstitution. Blood 101(1):112–118PubMedCrossRefPubMedCentralGoogle Scholar
  16. Darwish NH, Sudha T, Godugu K, Elbaz O, Abdelghaffar HA, Hassan EE et al (2016) Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1. Oncotarget 7(36):57811–57820PubMedPubMedCentralCrossRefGoogle Scholar
  17. Dohner H, Weisdorf DJ, Bloomfield CD (2015) Acute Myeloid leukemia. N Engl J Med 373(12):1136–1152PubMedCrossRefPubMedCentralGoogle Scholar
  18. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447PubMedPubMedCentralCrossRefGoogle Scholar
  19. Du W, Hu Y, Lu C, Li J, Liu W, He Y et al (2015) Cluster of differentiation 96 as a leukemia stem cell-specific marker and a factor for prognosis evaluation in leukemia. Mol Clin Oncol 3(4):833–838PubMedPubMedCentralCrossRefGoogle Scholar
  20. Emamdoost F, Khanahmad H, Ganjalikhani-Hakemi M, Doosti A (2017) The miR-125a-3p inhibits TIM-3 expression in AML cell line HL-60 in vitro. Indian J Hematol Blood Transfusion 33(3):342–347CrossRefGoogle Scholar
  21. Fialkow PJ, Gartler SM, Yoshida A (1967) Clonal origin of chronic myelocytic leukemia in man. Proc Natl Acad Sci U S A 58(4):1468–1471PubMedPubMedCentralCrossRefGoogle Scholar
  22. Fooladinezhad H, Khanahmad H, Ganjalikhani-Hakemi M, Doosti A (2016) Negative regulation of TIM-3 expression in AML cell line (HL-60) using miR-330-5p. Br J Biomed Sci 73(3):129–133PubMedCrossRefPubMedCentralGoogle Scholar
  23. Fujiwara SI, Muroi K, Yamamoto C, Hatano K, Okazuka K, Sato K et al (2017) CD25 as an adverse prognostic factor in elderly patients with acute myeloid leukemia. Hematology 22(6):347–353PubMedCrossRefPubMedCentralGoogle Scholar
  24. Gasparetto M, Sekulovic S, Zakaryan A, Imren S, Kent DG, Humphries RK et al (2012) Varying levels of aldehyde dehydrogenase activity in adult murine marrow hematopoietic stem cells are associated with engraftment and cell cycle status. Exp Hematol 40(10):857–66.e5PubMedCrossRefPubMedCentralGoogle Scholar
  25. Gerber JM, Smith BD, Ngwang B, Zhang H, Vala MS, Morsberger L et al (2012) A clinically relevant population of leukemic CD34(+)CD38(−) cells in acute myeloid leukemia. Blood 119(15):3571–3577PubMedPubMedCentralCrossRefGoogle Scholar
  26. Gerber JM, Zeidner JF, Morse S, Blackford AL, Perkins B, Yanagisawa B et al (2016) Association of acute myeloid leukemia’s most immature phenotype with risk groups and outcomes. Haematologica 101(5):607–616PubMedPubMedCentralCrossRefGoogle Scholar
  27. Giles F, Estey E, O’Brien S (2003) Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Cancer 98(10):2095–2104PubMedCrossRefPubMedCentralGoogle Scholar
  28. Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S et al (2011) Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19(1):138–152PubMedCrossRefPubMedCentralGoogle Scholar
  29. Gonen M, Sun Z, Figueroa ME, Patel JP, Abdel-Wahab O, Racevskis J et al (2012) CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood 120(11):2297–2306PubMedPubMedCentralCrossRefGoogle Scholar
  30. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 92(7):2322–2333PubMedPubMedCentralGoogle Scholar
  31. Grove CS, Vassiliou GS (2014) Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis Model Mech 7(8):941–951PubMedPubMedCentralCrossRefGoogle Scholar
  32. Hoang VT, Buss EC, Wang W, Hoffmann I, Raffel S, Zepeda-Moreno A et al (2015) The rarity of ALDH(+) cells is the key to separation of normal versus leukemia stem cells by ALDH activity in AML patients. Int J Cancer 137(3):525–536PubMedPubMedCentralCrossRefGoogle Scholar
  33. Hosen N, Park CY, Tatsumi N, Oji Y, Sugiyama H, Gramatzki M et al (2007) CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci U S A 104(26):11008–11013PubMedPubMedCentralCrossRefGoogle Scholar
  34. Huff CA, Matsui W, Smith BD, Jones RJ (2006) The paradox of response and survival in cancer therapeutics. Blood 107(2):431–434PubMedPubMedCentralCrossRefGoogle Scholar
  35. Hwang K, Park CJ, Jang S, Chi HS, Kim DY, Lee JH et al (2012) Flow cytometric quantification and immunophenotyping of leukemic stem cells in acute myeloid leukemia. Ann Hematol 91(10):1541–1546PubMedCrossRefPubMedCentralGoogle Scholar
  36. Ikegawa S, Doki N, Kurosawa S, Yamaguchi T, Sakaguchi M, Harada K et al (2016) CD25 expression on residual leukemic blasts at the time of allogeneic hematopoietic stem cell transplant predicts relapse in patients with acute myeloid leukemia without complete remission. Leuk Lymphoma 57(6):1375–1381PubMedCrossRefGoogle Scholar
  37. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R et al (2009) CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138(2):271–285PubMedPubMedCentralCrossRefGoogle Scholar
  38. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300PubMedCrossRefGoogle Scholar
  39. Jiang Y, Xu P, Yao D, Chen X, Dai H (2017) CD33, CD96 and Death Associated Protein Kinase (DAPK) expression are associated with the survival rate and/or response to the chemotherapy in the patients with Acute Myeloid Leukemia (AML). Med Sci Monit Int Med J Exp Clin Res 23:1725–1732Google Scholar
  40. Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL et al (2000) The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14(10):1777–1784PubMedCrossRefPubMedCentralGoogle Scholar
  41. Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H et al (2010) TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 7(6):708–717PubMedCrossRefPubMedCentralGoogle Scholar
  42. Klco JM, Spencer DH, Miller CA, Griffith M, Lamprecht TL, O’Laughlin M et al (2014) Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell 25(3):379–392PubMedPubMedCentralCrossRefGoogle Scholar
  43. Kreso A, Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14(3):275–291CrossRefGoogle Scholar
  44. Laborda E, Mazagova M, Shao S, Wang X, Quirino H, Woods AK et al (2017) Development of a chimeric antigen receptor targeting C-type lectin-like molecule-1 for human Acute Myeloid Leukemia. Int J Mol Sci 18(11):2259PubMedCentralCrossRefGoogle Scholar
  45. Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ (2011) Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475(7354):53–58PubMedCrossRefPubMedCentralGoogle Scholar
  46. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367(6464):645–648CrossRefGoogle Scholar
  47. Leong SR, Sukumaran S, Hristopoulos M, Totpal K, Stainton S, Lu E et al (2017) An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia. Blood 129(5):609–618PubMedPubMedCentralCrossRefGoogle Scholar
  48. Li F, Sutherland MK, Yu C, Walter RB, Westendorf L, Valliere-Douglass J et al (2018) Characterization of SGN-CD123A, a potent CD123-directed antibody-drug conjugate for Acute Myeloid Leukemia. Mol Cancer Ther 17(2):554–564PubMedCrossRefPubMedCentralGoogle Scholar
  49. Lowenberg B, Downing JR, Burnett A (1999) Acute myeloid leukemia. N Engl J Med 341(14):1051–1062PubMedCrossRefPubMedCentralGoogle Scholar
  50. Majeti R (2011) Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells. Oncogene 30(9):1009–1019PubMedCrossRefPubMedCentralGoogle Scholar
  51. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr et al (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138(2):286–299PubMedPubMedCentralCrossRefGoogle Scholar
  52. Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE et al (2013) T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood 122(18):3138–3148PubMedPubMedCentralCrossRefGoogle Scholar
  53. Martelli MP, Pettirossi V, Thiede C, Bonifacio E, Mezzasoma F, Cecchini D et al (2010) CD34+ cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice. Blood 116(19):3907–3922PubMedCrossRefPubMedCentralGoogle Scholar
  54. Maynadie M, De Angelis R, Marcos-Gragera R, Visser O, Allemani C, Tereanu C et al (2013) Survival of European patients diagnosed with myeloid malignancies: a HAEMACARE study. Haematologica 98(2):230–238PubMedPubMedCentralCrossRefGoogle Scholar
  55. Medeiros BC, Othus M, Fang M, Appelbaum FR, Erba HP (2015) Cytogenetic heterogeneity negatively impacts outcomes in patients with acute myeloid leukemia. Haematologica 100(3):331–335PubMedPubMedCentralCrossRefGoogle Scholar
  56. Mohseni Nodehi S, Repp R, Kellner C, Brautigam J, Staudinger M, Schub N et al (2012) Enhanced ADCC activity of affinity maturated and fc-engineered mini-antibodies directed against the AML stem cell antigen CD96. PLoS One 7(8):e42426PubMedPubMedCentralCrossRefGoogle Scholar
  57. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415(6871):536–541PubMedCrossRefPubMedCentralGoogle Scholar
  58. Muramoto GG, Russell JL, Safi R, Salter AB, Himburg HA, Daher P et al (2010) Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity. Stem Cells 28(3):523–534PubMedPubMedCentralGoogle Scholar
  59. Pearce DJ, Taussig D, Simpson C, Allen K, Rohatiner AZ, Lister TA et al (2005) Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples. Stem Cells 23(6):752–760PubMedCrossRefPubMedCentralGoogle Scholar
  60. Pearce DJ, Taussig D, Zibara K, Smith LL, Ridler CM, Preudhomme C et al (2006) AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML. Blood 107(3):1166–1173PubMedPubMedCentralCrossRefGoogle Scholar
  61. Pelosi E, Castelli G, Testa U (2015) Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells. Blood Cells Mol Dis 55(4):336–346PubMedCrossRefPubMedCentralGoogle Scholar
  62. Pizzitola I, Anjos-Afonso F, Rouault-Pierre K, Lassailly F, Tettamanti S, Spinelli O et al (2014) Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Leukemia 28(8):1596–1605PubMedCrossRefPubMedCentralGoogle Scholar
  63. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S et al (2002) Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 100(8):2717–2723PubMedCrossRefPubMedCentralGoogle Scholar
  64. Quek L, Otto GW (2016) Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med 213(8):1513–1535PubMedPubMedCentralCrossRefGoogle Scholar
  65. Ran D, Schubert M, Pietsch L, Taubert I, Wuchter P, Eckstein V et al (2009) Aldehyde dehydrogenase activity among primary leukemia cells is associated with stem cell features and correlates with adverse clinical outcomes. Exp Hematol 37(12):1423–1434PubMedCrossRefPubMedCentralGoogle Scholar
  66. Ran D, Schubert M, Taubert I, Eckstein V, Bellos F, Jauch A et al (2012) Heterogeneity of leukemia stem cell candidates at diagnosis of acute myeloid leukemia and their clinical significance. Exp Hematol 40(2):155–65.e1PubMedCrossRefPubMedCentralGoogle Scholar
  67. Riccioni R, Diverio D, Riti V, Buffolino S, Mariani G, Boe A et al (2009) Interleukin (IL)-3/granulocyte macrophage-colony stimulating factor/IL-5 receptor alpha and beta chains are preferentially expressed in acute myeloid leukaemias with mutated FMS-related tyrosine kinase 3 receptor. Br J Haematol 144(3):376–387PubMedCrossRefPubMedCentralGoogle Scholar
  68. Rollins-Raval M, Pillai R, Warita K, Mitsuhashi-Warita T, Mehta R, Boyiadzis M et al (2013) CD123 immunohistochemical expression in acute myeloid leukemia is associated with underlying FLT3-ITD and NPM1 mutations. Appl Immunohistochem Mol Morphol 21(3):212–217PubMedPubMedCentralGoogle Scholar
  69. Rombouts WJ, Martens AC, Ploemacher RE (2000) Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model. Leukemia 14(5):889–897PubMedCrossRefPubMedCentralGoogle Scholar
  70. Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S et al (2010) Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med 2(17):17ra9PubMedPubMedCentralCrossRefGoogle Scholar
  71. Sakaguchi S (2011) Regulatory T cells: history and perspective. Methods Mol Biol 707:3–17PubMedCrossRefPubMedCentralGoogle Scholar
  72. Sarry JE, Murphy K, Perry R, Sanchez PV, Secreto A, Keefer C et al (2011) Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rgammac-deficient mice. J Clin Investig 121(1):384–395PubMedCrossRefPubMedCentralGoogle Scholar
  73. Sato N, Caux C, Kitamura T, Watanabe Y, Arai K, Banchereau J et al (1993) Expression and factor-dependent modulation of the interleukin-3 receptor subunits on human hematopoietic cells. Blood 82(3):752–761PubMedPubMedCentralGoogle Scholar
  74. Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A et al (2013) Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med 56:89–101PubMedCrossRefPubMedCentralGoogle Scholar
  75. Su M, Alonso S, Jones JW, Yu J, Kane MA, Jones RJ et al (2015) All-trans retinoic acid activity in acute myeloid Leukemia: role of cytochrome P450 enzyme expression by the microenvironment. PLoS One 10(6):e0127790PubMedPubMedCentralCrossRefGoogle Scholar
  76. Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R et al (2005) Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood 106(8):2854–2861PubMedCrossRefPubMedCentralGoogle Scholar
  77. Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G et al (2005) Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106(13):4086–4092PubMedPubMedCentralCrossRefGoogle Scholar
  78. Taussig DC, Vargaftig J, Miraki-Moud F, Griessinger E, Sharrock K, Luke T et al (2010) Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(−) fraction. Blood 115(10):1976–1984PubMedPubMedCentralCrossRefGoogle Scholar
  79. Terwijn M, Zeijlemaker W, Kelder A, Rutten AP, Snel AN, Scholten WJ et al (2014) Leukemic stem cell frequency: a strong biomarker for clinical outcome in acute myeloid leukemia. PLoS One 9(9):e107587PubMedPubMedCentralCrossRefGoogle Scholar
  80. Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P et al (2002) Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood 100(8):2980–2988PubMedCrossRefPubMedCentralGoogle Scholar
  81. Testa U, Pelosi E, Frankel A (2014) CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. Biomarker Res 2(1):4CrossRefGoogle Scholar
  82. Tsimberidou AM, Estey E, Cortes JE, Garcia-Manero G, Faderl S, Verstovsek S et al (2003) Mylotarg, fludarabine, cytarabine (ara-C), and cyclosporine (MFAC) regimen as post-remission therapy in acute myelogenous leukemia. Cancer Chemother Pharmacol 52(6):449–452PubMedCrossRefPubMedCentralGoogle Scholar
  83. van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B et al (2007) The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 110(7):2659–2666PubMedCrossRefPubMedCentralGoogle Scholar
  84. Venton G, Perez-Alea M, Baier C, Fournet G, Quash G, Labiad Y et al (2016) Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors. Blood Cancer J 6(9):e469PubMedPubMedCentralCrossRefGoogle Scholar
  85. Vergez F, Green AS, Tamburini J, Sarry JE, Gaillard B, Cornillet-Lefebvre P et al (2011) 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 96(12):1792–1798PubMedPubMedCentralCrossRefGoogle Scholar
  86. Walter RB, Appelbaum FR, Estey EH, Bernstein ID (2012) Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 119(26):6198–6208PubMedPubMedCentralCrossRefGoogle Scholar
  87. Wang PL, O’Farrell S, Clayberger C, Krensky AM (1992) Identification and molecular cloning of tactile. A novel human T cell activation antigen that is a member of the Ig gene superfamily. J Immunol 148(8):2600–2608PubMedPubMedCentralGoogle Scholar
  88. Wang J, Chen S, Xiao W, Li W, Wang L, Yang S et al (2018) CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia. J Hematol Oncol 11(1):7PubMedPubMedCentralCrossRefGoogle Scholar
  89. Warmerdam PA, Parren PW, Vlug A, Aarden LA, van de Winkel JG, Capel PJ (1992) Polymorphism of the human Fc gamma receptor II (CD32): molecular basis and functional aspects. Immunobiology 185(2–4):175–182PubMedCrossRefPubMedCentralGoogle Scholar
  90. Xie LH, Biondo M, Busfield SJ, Arruda A, Yang X, Vairo G et al (2017) CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission. Blood Cancer J 7(6):e567PubMedPubMedCentralCrossRefGoogle Scholar
  91. Xu L, Xu J, Ma S, Li X, Zhu M, Chen S et al (2017a) High Tim-3 expression on AML blasts could enhance chemotherapy sensitivity. Oncotarget 8(60):102088–102096PubMedPubMedCentralGoogle Scholar
  92. Xu B, Wang S, Li R, Chen K, He L, Deng M et al (2017b) Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-kappaB and Nrf2. Cell Death Dis 8(5):e2797PubMedPubMedCentralCrossRefGoogle Scholar
  93. Yabushita T, Satake H (2017) Expression of multiple leukemic stem cell markers is associated with poor prognosis in de novo acute myeloid leukemia. 1–8 Leuk Lymphoma 59(9):2144–2151CrossRefGoogle Scholar
  94. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T (2005) Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19(8):1345–1349PubMedCrossRefPubMedCentralGoogle Scholar
  95. Yanada M, Mori J, Aoki J, Harada K, Mizuno S, Uchida N et al (2018) Effect of cytogenetic risk status on outcomes for patients with acute myeloid leukemia undergoing various types of allogeneic hematopoietic cell transplantation: an analysis of 7812 patients. Leuk Lymphoma 59(3):601–609PubMedCrossRefPubMedCentralGoogle Scholar
  96. Yanagisawa B, Ghiaur G, Smith BD, Jones RJ (2016) Translating leukemia stem cells into the clinical setting: harmonizing the heterogeneity. Exp Hematol 44(12):1130–1137PubMedPubMedCentralCrossRefGoogle Scholar
  97. Yang CK, Wang XK, Liao XW, Han CY, Yu TD, Qin W et al (2017) Aldehyde dehydrogenase 1 (ALDH1) isoform expression and potential clinical implications in hepatocellular carcinoma. PloS one 12(8):e0182208PubMedPubMedCentralCrossRefGoogle Scholar
  98. Yang X, Yao R, Wang H (2018) Update of ALDH as a potential biomarker and therapeutic target for AML. BioMed Res Int 2018:9192104PubMedPubMedCentralGoogle Scholar
  99. Zeijlemaker W, Kelder A, Wouters R, Valk PJM, Witte BI, Cloos J et al (2015) Absence of leukaemic CD34(+) cells in acute myeloid leukaemia is of high prognostic value: a longstanding controversy deciphered. Br J Haematol 171(2):227–238PubMedCrossRefPubMedCentralGoogle Scholar
  100. Zheng B, Yu SF, Del Rosario G, Leong SR, Lee GY, Vij R et al (2018) An anti-CLL-1 antibody-drug conjugate for the treatment of Acute Myeloid Leukemia. Clin Cancer Res 25(4):1358–1368PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA

Personalised recommendations