Re-evaluation of various molecular targets located on CD34+CD38-Lin- leukemia stem cells and other cell subsets in pediatric acute myeloid leukemia

Cheng,Yuping; Jia,Ming; Chen,Yuanyuan; Zhao,Haizhao; Luo,Zebin; Tang,Yongmin

doi:10.3892/ol.2015.3972

Re-evaluation of various molecular targets located on CD34+CD38-Lin- leukemia stem cells and other cell subsets in pediatric acute myeloid leukemia

Authors:
- Yuping Cheng
- Ming Jia
- Yuanyuan Chen
- Haizhao Zhao
- Zebin Luo
- Yongmin Tang
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Affiliations: Department of Hematology-Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
Published online on: November 25, 2015 https://doi.org/10.3892/ol.2015.3972
Pages: 891-897

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Abstract

Leukemia stem cells (LSCs) are hypothesized to be capable of driving the development of leukemia, and are responsible for disease relapse. Antibody therapy targeting cell surface antigens has significantly improved the treatment outcomes of leukemia. Therefore, it is important to identify cell surface markers that are expressed on LSCs, and that are unexpressed or expressed at reduced levels on normal hematopoietic stem cells (HSCs), in order to establish novel therapeutic targets. In the present study, the immunophenotypic characteristics of cluster of differentiation (CD)34+CD38‑lineage (Lin)‑ stem cells were analyzed, and antigen expression levels were compared with the expression of other cell components, using multicolor flow cytometry, in 54 patients with newly diagnosed acute myeloid leukemia (AML) and 11 control patients with immune thrombocytopenia. The findings indicated that CD133 and human leukocyte antigen (HLA)‑DR were expressed on normal HSCs and on AML LSCs, with no significant difference (P>0.05). By contrast, CD33, CD123 and CD44 were highly expressed on AML LSCs, and demonstrated significant differences compared with their expression on normal HSCs (CD33, 81.7 vs. 18.3%; CD123, 75.8 vs. 19.1%; CD44, 97.7 vs. 84.4%). Among the aforementioned antigens, CD33 and CD123 were promising candidates for targeted therapy for the treatment of AML. This was particularly evident for CD123 in immature AML subtype cells, which may require additional investigation within a clinical trial setting. CD44, CD133 and HLA‑DR may not be suitable for leukemia targeting due to their broad and high expression levels on normal HSCs and other tissues.

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1	Linabery AM and Ross JA: Trends in childhood cancer incidence in the U.S. (1992–2004). Cancer. 112:416–432. 2008. View Article : Google Scholar : PubMed/NCBI
2	Barth M, Raetz E and Cairo MS: The future role of monoclonal antibody therapy in childhood acute leukaemias. Br J Haematol. 159:3–17. 2012. View Article : Google Scholar : PubMed/NCBI
3	Gorman MF, Ji L, Ko RH, et al: Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): A Therapeutic Advances in Childhood Leukemia (TACL) Consortium study. Pediatr Blood Cancer. 55:421–429. 2010. View Article : Google Scholar : PubMed/NCBI
4	Huntly BJ and Gilliland DG: Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 5:311–321. 2005. View Article : Google Scholar : PubMed/NCBI
5	Bonnet D and Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 3:730–737. 1997. View Article : Google Scholar : PubMed/NCBI
6	Hauswirth AW, Florian S, Printz D, Sotlar K, Krauth MT, Fritsch G, Schernthaner GH, Wacheck V, Selzer E, Sperr WR and Valent P: Expression of the target receptor CD33 in CD34⁺/CD38⁻/CD123⁺ AML stem cells. Eur J Clin Invest. 37:73–82. 2007. View Article : Google Scholar : PubMed/NCBI
7	Jin L, Hope KJ, Zhai Q, Smadja-Joffe F and Dick JE: Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 12:1167–1174. 2006. View Article : Google Scholar : PubMed/NCBI
8	Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, Meyerrose T, Rossi R, Grimes B, Rizzieri DA, et al: The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 14:1777–1784. 2000. View Article : Google Scholar : PubMed/NCBI
9	Toren A, Bielorai B, Jacob-Hirsch J, Fisher T, Kreiser D, Moran O, Zeligson S, Givol D, Yitzhaky A, Itskovitz-Eldor J, et al: CD133-positive hematopoietic stem cell ‘stemness’ genes contain many genes mutated or abnormally expressed in leukemia. Stem Cells. 23:1142–1153. 2005. View Article : Google Scholar : PubMed/NCBI
10	Saito Y, Kitamura H, Hijikata A, et al: Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med. 2:17ra92010. View Article : Google Scholar : PubMed/NCBI
11	Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, van Rooijen N and Weissman IL: CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 138:286–299. 2009. View Article : Google Scholar : PubMed/NCBI
12	van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, Stigter-van Walsum M, Zweegman S, Ossenkoppele GJ and Jan Schuurhuis G: The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 110:2659–2666. 2007. View Article : Google Scholar : PubMed/NCBI
13	Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G, Luongo JL, Danet-Desnoyers GA and Bonnet D: Hematopoietic stem cells express multiple myeloid markers: Implications for the origin and targeted therapy of acute myeloid leukemia. Blood. 106:4086–4092. 2005. View Article : Google Scholar : PubMed/NCBI
14	Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J and Buck DW: AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 90:5002–5012. 1997.PubMed/NCBI
15	Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, Lahey R, Eades WC, Creer MH and Nolta JA: Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood. 107:2162–2169. 2006. View Article : Google Scholar : PubMed/NCBI
16	Scott AM, Wolchok JD and Old LJ: Antibody therapy of cancer. Nat Rev Cancer. 12:278–287. 2012. View Article : Google Scholar : PubMed/NCBI
17	Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR and Sultan C: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 33:451–458. 1976. View Article : Google Scholar : PubMed/NCBI
18	Heerema-McKenney A and Arber DA: Acute myeloid leukemia. Hematol Oncol Clin North Am. 23:633–654. 2009. View Article : Google Scholar : PubMed/NCBI
19	Human Experimentation. Code of Ethics of the World Medical Association (Declaration of Helsinki). Can Med Assoc J. 91:6191964.PubMed/NCBI
20	Paietta E: Expression of cell-surface antigens in acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 16:369–385. 2003. View Article : Google Scholar : PubMed/NCBI
21	Beckman RA, Weiner LM and Davis HM: Antibody constructs in cancer therapy: Protein engineering strategies to improve exposure in solid tumors. Cancer. 109:170–179. 2007. View Article : Google Scholar : PubMed/NCBI
22	Laszlo GS, Estey EH and Walter RB: The past and future of CD33 as therapeutic target in acute myeloid leukemia. Blood Rev. 28:143–153. 2014. View Article : Google Scholar : PubMed/NCBI
23	Pizzitola I, Anjos-Afonso F, Rouault-Pierre K, Lassailly F, Tettamanti S, Spinelli O, Biondi A, Biagi E and Bonnet D: Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Leukemia. 28:1596–1605. 2014. View Article : Google Scholar : PubMed/NCBI
24	Dutour A, Marin V, Pizzitola I, Valsesia-Wittmann S, Lee D, Yvon E, Finney H, Lawson A, Brenner M, Biondi A, et al: In vitro and in vivo antitumor effect of anti-CD33 chimeric receptor-expressing EBV-CTL against CD33 acute myeloid leukemia. Adv Hematol. 2012:6830652012. View Article : Google Scholar : PubMed/NCBI
25	Laszlo GS, Gudgeon CJ, Harrington KH, Dell'Aringa J, Newhall KJ, Means GD, Sinclair AM, Kischel R, Frankel SR and Walter RB: Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. Blood. 123:554–561. 2014. View Article : Google Scholar : PubMed/NCBI
26	Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, Ryan MC, Sussman D, Lyon RP, et al: SGN-CD33A: A novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 122:1455–1463. 2013. View Article : Google Scholar : PubMed/NCBI
27	Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, et al: Acute Leukemia French Association: Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study. Lancet. 379:1508–1516. 2012. View Article : Google Scholar : PubMed/NCBI
28	Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, et al: Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 30:3924–3931. 2012. View Article : Google Scholar : PubMed/NCBI
29	Du X, Ho M and Pastan I: New immunotoxins targeting CD123, a stem cell antigen on acute myeloid leukemia cells. J Immunother. 30:607–613. 2007. View Article : Google Scholar : PubMed/NCBI
30	Testa U, Fossati C, Samoggia P, Masciulli R, et al: Expression of growth factor receptors in unilineage differentiation culture of purified hematopoietic progenitors. Blood. 88:3391–3406. 1996.PubMed/NCBI
31	Busfield SJ, Biondo M, Wong M, Ramshaw HS, Lee EM, Ghosh S, Braley H, Panousis C, Roberts AW, He SZ, et al: Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC. Leukemia. 28:2213–2221. 2014. View Article : Google Scholar : PubMed/NCBI
32	Mahnke YD, Brodie TM, Sallusto F, Roederer M and Lugli E: The who's who of T-cell differentiation: Human memory T-cell subsets. Eur J Immunol. 43:2797–2809. 2013. View Article : Google Scholar : PubMed/NCBI
33	Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA and Rafii S: Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 95:952–958. 2000.PubMed/NCBI
34	Pfenninger CV, Roschupkina T, Hertwig F, Kottwitz D, Englund E, Bengzon J, Jacobsen SE and Nuber UA: CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells. Cancer Res. 67:5727–5736. 2007. View Article : Google Scholar : PubMed/NCBI
35	Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK and Buck DW: A novel five-transmembrane hematopoietic stem cell antigen: Isolation, characterization, and molecular cloning. Blood. 90:5013–5021. 1997.PubMed/NCBI
36	van Gosliga D, Schepers H, Rizo A, van der Kolk D, Vellenga E and Schuringa JJ: Establishing long-term cultures with self-renewing acute myeloid leukemia stem/progenitor cells. Exp Hematol. 35:1538–1549. 2007. View Article : Google Scholar : PubMed/NCBI