{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:11:28Z","timestamp":1760148688605,"version":"build-2065373602"},"reference-count":117,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust","award":["IR5\\1018"],"award-info":[{"award-number":["IR5\\1018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60\u201375% but fall to 5\u201315% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful.<\/jats:p>","DOI":"10.3390\/ijms24119667","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T10:08:41Z","timestamp":1685700521000},"page":"9667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"24","author":[{"given":"Vanessa S.","family":"Morris","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Hull, Kingston upon Hull HU6 7RX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanya","family":"Ghazi","sequence":"additional","affiliation":[{"name":"Hull York Medical School, University of Hull, Kingston upon Hull HU6 7RX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6847-841X","authenticated-orcid":false,"given":"Daniel M.","family":"Fletcher","sequence":"additional","affiliation":[{"name":"Centre for Biomedicine, Hull York Medical School, Kingston upon Hull HU6 7RX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-4541","authenticated-orcid":false,"given":"Barbara-ann","family":"Guinn","sequence":"additional","affiliation":[{"name":"Centre for Biomedicine, Hull York Medical School, Kingston upon Hull HU6 7RX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5280","DOI":"10.1038\/s41467-018-07584-1","article-title":"Age-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias","volume":"9","author":"Chaudhury","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1038\/bcj.2016.50","article-title":"Acute myeloid leukemia: A comprehensive review and 2016 update","volume":"6","year":"2016","journal-title":"Blood Cancer J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S0140-6736(18)31041-9","article-title":"Acute myeloid leukaemia","volume":"392","author":"Short","year":"2018","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nrg.2016.13","article-title":"Epigenetic modulators, modifiers and mediators in cancer aetiology and progression","volume":"17","author":"Feinberg","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1080\/10428194.2021.1907372","article-title":"Tumor suppressors in acute myeloid leukemia","volume":"62","author":"Wallwitz","year":"2021","journal-title":"Leuk. Lymphoma"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101094","DOI":"10.1016\/j.beha.2019.101094","article-title":"Will new agents impact survival in AML?","volume":"32","author":"Rowe","year":"2019","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1182\/blood-2016-10-696039","article-title":"Therapeutic targeting of acute myeloid leukemia stem cells","volume":"129","author":"Pollyea","year":"2017","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Greiner, J. (2019). The Important Role of Immunotherapies in Acute Myeloid Leukemia. J. Clin. Med., 8.","DOI":"10.3390\/jcm8122054"},{"key":"ref_9","unstructured":"(2023, April 25). NCI Immunotherapy Agent Workshop, Available online: http:\/\/dcb.nci.nih.gov\/ImmunAgentWork."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5323","DOI":"10.1158\/1078-0432.CCR-09-0737","article-title":"The prioritization of cancer antigens: A national cancer institute pilot project for the acceleration of translational research","volume":"15","author":"Cheever","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Saaty, T.L. (1980). The Analytic Hierarchy Process: Planning, Priority Setting, Resource Allocation, McGraw-Hill.","DOI":"10.21236\/ADA214804"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/leu.2016.254","article-title":"PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies","volume":"31","author":"Qazilbash","year":"2017","journal-title":"Leukemia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1007\/s11899-018-0463-9","article-title":"Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes","volume":"13","author":"Ivy","year":"2018","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.3324\/haematol.2020.259457","article-title":"Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model","volume":"106","author":"Stroopinsky","year":"2021","journal-title":"Haematologica"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/j.1365-2141.1976.tb03563.x","article-title":"Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group","volume":"33","author":"Bennett","year":"1976","journal-title":"Br. J. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/(SICI)1099-1069(199711)15:4<173::AID-HON610>3.0.CO;2-K","article-title":"Age and sex distributions of hematological malignancies in the U.K.","volume":"15","author":"McNally","year":"1997","journal-title":"Hematol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., and Group, P. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wohlin, C. (2014, January 13\u201314). Guidelines for snowballing in systematic literature studies and a replication in software engineering. Proceedings of the 18th International Conference on Evaluation and Assessment in Software Engineering, London, UK.","DOI":"10.1145\/2601248.2601268"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"529","DOI":"10.7326\/0003-4819-155-8-201110180-00009","article-title":"QUADAS-2: A revised tool for the quality assessment of diagnostic accuracy studies","volume":"155","author":"Whiting","year":"2011","journal-title":"Ann. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/1476-4598-9-242","article-title":"A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12","volume":"9","author":"Klinke","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1182\/blood-2007-04-082099","article-title":"A critical role for Lyn in acute myeloid leukemia","volume":"111","author":"Demur","year":"2008","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.leukres.2009.01.041","article-title":"Aberrant expression of TSC2 gene in the newly diagnosed acute leukemia","volume":"33","author":"Xu","year":"2009","journal-title":"Leuk. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57811","DOI":"10.18632\/oncotarget.11063","article-title":"Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: Potential impact of BMI-1, TIM-3 and CLL-1","volume":"7","author":"Darwish","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8547","DOI":"10.2147\/CMAR.S210504","article-title":"ADAR1 may be involved in the proliferation of acute myeloid leukemia cells via regulation of the Wnt pathway","volume":"11","author":"Xiao","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8457","DOI":"10.1002\/cam4.3467","article-title":"Characteristics and prognostic significance of genetic mutations in acute myeloid leukemia based on a targeted next-generation sequencing technique","volume":"9","author":"Wang","year":"2020","journal-title":"Cancer Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1080\/16078454.2020.1720102","article-title":"Clinical features and prognosis of normal karyotype acute myeloid leukemia pediatric patients with WT1 mutations: An analysis based on TCGA database","volume":"25","author":"Xu","year":"2020","journal-title":"Hematology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/s41375-018-0180-3","article-title":"Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML","volume":"33","author":"Haubner","year":"2019","journal-title":"Leukemia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"867","DOI":"10.2147\/IJGM.S276138","article-title":"Combined Expression of CD34 and FLT3-Internal Tandem Duplication Mutation Predicts Poor Response to Treatment in Acute Myeloid Leukemia","volume":"13","author":"Abdellateif","year":"2020","journal-title":"Int. J. Gen. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1046\/j.1365-2141.2003.04212.x","article-title":"Expression of human leucocyte antigens and co-stimulatory molecules on blasts of patients with acute myeloid leukaemia","volume":"120","author":"Vollmer","year":"2003","journal-title":"Br. J. Haematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s12967-017-1279-4","article-title":"Gene mutational pattern and expression level in 560 acute myeloid leukemia patients and their clinical relevance","volume":"15","author":"Zhu","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.leukres.2015.02.009","article-title":"Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK\/c-JUN signaling pathway","volume":"39","author":"Lin","year":"2015","journal-title":"Leuk. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1007\/s00277-015-2413-0","article-title":"HES1 activation suppresses proliferation of leukemia cells in acute myeloid leukemia","volume":"94","author":"Tian","year":"2015","journal-title":"Ann. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102088","DOI":"10.18632\/oncotarget.22141","article-title":"High Tim-3 expression on AML blasts could enhance chemotherapy sensitivity","volume":"8","author":"Xu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"470","DOI":"10.12669\/pjms.35.2.614","article-title":"Immunophenotypic characterisation of morphologically diagnosed cases of Acute Myeloid Leukaemia (AML)","volume":"35","author":"Basharat","year":"2019","journal-title":"Pak. J. Med. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41375-019-0596-4","article-title":"Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia","volume":"34","author":"Alanazi","year":"2020","journal-title":"Leukemia"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Greiner, J., Brown, E., Bullinger, L., Hills, R.K., Morris, V., Dohner, H., Mills, K.I., and Guinn, B.A. (2021). Survivin\u2019 Acute Myeloid Leukaemia-A Personalised Target for inv(16) Patients. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910482"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"54825","DOI":"10.18632\/oncotarget.10240","article-title":"Mutation profiling of 19 candidate genes in acute myeloid leukemia suggests significance of DNMT3A mutations","volume":"7","author":"Shin","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1533033820965580","DOI":"10.1177\/1533033820965580","article-title":"Oncogenic Long Noncoding RNA DARS-AS1 in Childhood Acute Myeloid Leukemia by Binding to microRNA-425","volume":"19","author":"Dou","year":"2020","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1038\/sj.leu.2402534","article-title":"Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia","volume":"16","author":"Padro","year":"2002","journal-title":"Leukemia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1002\/ajh.25255","article-title":"P53 protein overexpression in de novo acute myeloid leukemia patients with normal diploid karyotype correlates with FLT3 internal tandem duplication and worse relapse-free survival","volume":"93","author":"Assi","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/sj.leu.2401067","article-title":"Prognostic relevance of the expression of Tdt and CD7 in 335 cases of acute myeloid leukemia","volume":"12","author":"Venditti","year":"1998","journal-title":"Leukemia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1007\/s12032-011-0104-9","article-title":"Prognostic significance of CD56 antigen expression in patients with acute myeloid leukemia","volume":"29","author":"Djunic","year":"2012","journal-title":"Med. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6595","DOI":"10.1002\/cam4.2535","article-title":"Prognostic significance of CXCR4 expression in acute myeloid leukemia","volume":"8","author":"Du","year":"2019","journal-title":"Cancer Med."},{"key":"ref_46","first-page":"100203","article-title":"Prognostic value of CD25\/CD123 pattern of expression in acute myeloid leukemia patients with normal cytogenetic","volume":"13","author":"Aref","year":"2020","journal-title":"Leuk. Res. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/cncr.23219","article-title":"Prognostic value of immunophenotyping in elderly patients with acute myeloid leukemia: A single-institution experience","volume":"112","author":"Plesa","year":"2008","journal-title":"Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"891","DOI":"10.3892\/ol.2015.3972","article-title":"Re-evaluation of various molecular targets located on CD34(+)CD38(-)Lin(-) leukemia stem cells and other cell subsets in pediatric acute myeloid leukemia","volume":"11","author":"Cheng","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7367","DOI":"10.1111\/jcmm.16765","article-title":"Silencing of circTASP1 inhibits proliferation and induces apoptosis of acute myeloid leukaemia cells through modulating miR-515-5p\/HMGA2 axis","volume":"25","author":"Lin","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.1158\/1078-0432.CCR-20-4543","article-title":"Anti-CLL1 Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed\/Refractory Acute Myeloid Leukemia","volume":"27","author":"Zhang","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.3324\/haematol.2019.222612","article-title":"TARP is an immunotherapeutic target in acute myeloid leukemia expressed in the leukemic stem cell compartment","volume":"105","author":"Depreter","year":"2020","journal-title":"Haematologica"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"109","DOI":"10.30699\/jambs.29.133.109","article-title":"The prognostic impact of WT1 expression levels, mutations, and SNP rs16754 in AML patients: A retrospective cohort study","volume":"29","author":"Rostami","year":"2021","journal-title":"J. Adv. Med. Biomed. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1097\/CJI.0000000000000322","article-title":"WT1, PRAME, and PR3 mRNA Expression in Acute Myeloid Leukemia (AML)","volume":"43","author":"Steger","year":"2020","journal-title":"J. Immunother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1182\/blood.2020006921","article-title":"CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy","volume":"137","author":"Willier","year":"2021","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"18012","DOI":"10.1038\/s41598-021-97400-6","article-title":"DNAM-1\/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis","volume":"11","author":"Chashchina","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/cyto.b.21952","article-title":"Leukocyte immunoglobulin-like receptor B1 and B4 (LILRB1 and LILRB4): Highly sensitive and specific markers of acute myeloid leukemia with monocytic differentiation","volume":"100","author":"Churchill","year":"2021","journal-title":"Cytom. B Clin. Cytom."},{"key":"ref_57","first-page":"6643948","article-title":"C-Type Lectin-Like Molecule-1 as a Biomarker for Diagnosis and Prognosis in Acute Myeloid Leukemia: A Preliminary Study","volume":"2021","author":"Wang","year":"2021","journal-title":"Biomed. Res. Int."},{"key":"ref_58","first-page":"1929357","article-title":"Prognostic Significance of CD56 Antigen Expression in Patients with De Novo Non-M3 Acute Myeloid Leukemia","volume":"2021","author":"Sun","year":"2021","journal-title":"Biomed. Res. Int."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"D419","DOI":"10.1093\/nar\/gky1038","article-title":"PANTHER version 14: More genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools","volume":"47","author":"Mi","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"24627","DOI":"10.18632\/oncotarget.5685","article-title":"Age-related somatic mutations in the cancer genome","volume":"6","author":"Milholland","year":"2015","journal-title":"Oncotarget"},{"key":"ref_61","first-page":"114","article-title":"Lost in translation: Animal models and clinical trials in cancer treatment","volume":"6","author":"Mak","year":"2014","journal-title":"Am. J. Transl. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3389\/fonc.2018.00559","article-title":"Development of Severe Combined Immunodeficient (SCID) Pig Models for Translational Cancer Modeling: Future Insights on How Humanized SCID Pigs Can Improve Preclinical Cancer Research","volume":"8","author":"Boettcher","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.3389\/fonc.2020.01696","article-title":"Humanized Rodent Models for Cancer Research","volume":"10","author":"Tian","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Marsh, V., Mwangome, N., Jao, I., Wright, K., Molyneux, S., and Davies, A. (2019). Who should decide about children\u2019s and adolescents\u2019 participation in health research? The views of children and adults in rural Kenya. BMC Med. Ethics, 20.","DOI":"10.1186\/s12910-019-0375-9"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1182\/blood-2017-12-778472","article-title":"Treatment strategies for adolescent and young adult patients with acute myeloid leukemia","volume":"132","author":"Freyer","year":"2018","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"937087","DOI":"10.1100\/2012\/937087","article-title":"Expression and clinical significance of antiapoptotic gene (survivin) in NB4 and acute promyelocytic leukemia cells","volume":"2012","author":"Xue","year":"2012","journal-title":"Sci. World J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1080\/08880018.2018.1530702","article-title":"Expression of antiapoptotic proteins livin and survivin in pediatric AML patients, as prognostic markers","volume":"35","author":"Zareifar","year":"2018","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1007\/s12015-020-09995-4","article-title":"Emerging Importance of Survivin in Stem Cells and Cancer: The Development of New Cancer Therapeutics","volume":"16","author":"Warrier","year":"2020","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Ling, X., Cao, S., Cheng, Q., Keefe, J.T., Rustum, Y.M., and Li, F. (2012). A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045571"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1186\/s13046-018-0899-8","article-title":"An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer","volume":"37","author":"Ling","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1001\/jamainternmed.2017.3601","article-title":"Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval","volume":"177","author":"Prasad","year":"2017","journal-title":"JAMA Intern. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1182\/blood.2020005877","article-title":"Occupy BTK: The key to controlling CLL","volume":"136","author":"Thompson","year":"2020","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"656218","DOI":"10.3389\/fonc.2021.656218","article-title":"Immunotherapy in Acute Myeloid Leukemia: Where We Stand","volume":"11","author":"Isidori","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/s41591-019-0472-9","article-title":"T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant","volume":"25","author":"Chapuis","year":"2019","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1182\/blood.2019002779","article-title":"Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia","volume":"135","author":"He","year":"2020","journal-title":"Blood"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Tran, V.T., Phan, T.T., Mac, H.P., Tran, T.T., Ho, T.T., Pho, S.P., Nguyen, V.N., Vo, T.M., Nguyen, H.T., and Le, T.T. (2020). The diagnostic power of CD117, CD13, CD56, CD64, and MPO in rapid screening acute promyelocytic leukemia. BMC Res. Notes, 13.","DOI":"10.1186\/s13104-020-05235-7"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1096\/fj.11-181396","article-title":"Aminopeptidase-N\/CD13 is a potential proapoptotic target in human myeloid tumor cells","volume":"25","author":"Piedfer","year":"2011","journal-title":"FASEB J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/med.20044","article-title":"Aminopeptidase-N\/CD13 (EC 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospects","volume":"26","author":"Bauvois","year":"2005","journal-title":"Med. Res. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1179\/1607845413Y.0000000139","article-title":"Angiogenesis and acute myeloid leukemia","volume":"19","author":"Haouas","year":"2014","journal-title":"Hematology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fcvm.2017.00065","article-title":"Angiogenesis, Cancer, and Vascular Aging","volume":"4","author":"Moriya","year":"2017","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.18632\/oncotarget.1610","article-title":"WT1 regulates angiogenesis in Ewing Sarcoma","volume":"5","author":"Katuri","year":"2014","journal-title":"Oncotarget"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s12943-015-0467-1","article-title":"The twisted survivin connection to angiogenesis","volume":"14","author":"Sanhueza","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1634\/theoncologist.2014-0465","article-title":"Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor","volume":"20","author":"Zhao","year":"2015","journal-title":"Oncologist"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1056\/NEJMra1406184","article-title":"Acute Myeloid Leukemia","volume":"373","author":"Dohner","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.ccell.2015.04.004","article-title":"Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells","volume":"27","author":"Welner","year":"2015","journal-title":"Cancer Cell."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1016\/j.celrep.2017.03.018","article-title":"Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia","volume":"18","author":"Carey","year":"2017","journal-title":"Cell. Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1002\/mco2.147","article-title":"Role of chemokine systems in cancer and inflammatory diseases","volume":"3","author":"Li","year":"2022","journal-title":"MedComm"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41416-018-0328-y","article-title":"Cytokines in clinical cancer immunotherapy","volume":"120","author":"Berraondo","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.7314\/APJCP.2013.14.4.2439","article-title":"Associations of IL-10 gene polymorphisms with acute myeloid leukemia in Hunan, China","volume":"14","author":"Yao","year":"2013","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11693-015-9161-2","article-title":"TGF-beta signaling and its role in the regulation of hematopoietic stem cells","volume":"9","author":"Vaidya","year":"2015","journal-title":"Syst. Synth. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1182\/blood.2021014472","article-title":"Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome","volume":"139","author":"Grob","year":"2022","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/leu.2016.263","article-title":"The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: An analysis of 3307 cases","volume":"31","author":"Stengel","year":"2017","journal-title":"Leukemia"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Cluzeau, T., Loschi, M., Fenaux, P., Komrokji, R., and Sallman, D.A. (2021). Personalized Medicine for TP53 Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810105"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/jha2.441","article-title":"microRNA expression in acute myeloid leukaemia: New targets for therapy?","volume":"3","author":"Fletcher","year":"2022","journal-title":"EJHaem"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1182\/blood-2018-99-110319","article-title":"Acute Myeloid Leukemia (AML) with Somatic Mutations in PTPN11 Is Associated with Treatment Resistance and Poor Overall Survival","volume":"132","author":"Kaner","year":"2018","journal-title":"Blood"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1038\/sj.leu.2403492","article-title":"PTPN11 mutations in pediatric patients with acute myeloid leukemia: Results from the Children\u2019s Cancer Group","volume":"18","author":"Loh","year":"2004","journal-title":"Leukemia"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1182\/bloodadvances.2021006242","article-title":"Molecular, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia","volume":"6","author":"Fobare","year":"2022","journal-title":"Blood Adv."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.brainresrev.2004.12.006","article-title":"Cytokine-mediated inflammation, tumorigenesis, and disease-associated JAK\/STAT\/SOCS signaling circuits in the CNS","volume":"48","author":"Campbell","year":"2005","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"107186","DOI":"10.1016\/j.intimp.2020.107186","article-title":"JAK2 expression is correlated with the molecular and clinical features of breast cancer as a favorable prognostic factor","volume":"90","author":"Liu","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1038\/sj.leu.2404812","article-title":"JAK2-V617F activating mutation in acute myeloid leukemia: Prognostic impact and association with other molecular markers","volume":"21","author":"Vicente","year":"2007","journal-title":"Leukemia"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e11331","DOI":"10.1097\/MD.0000000000011331","article-title":"Essential thrombocythemia during treatment of acute myeloid leukemia with JAK2 V617F mutation: A case report of a CARE-compliant article","volume":"97","author":"Ding","year":"2018","journal-title":"Medicine"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1016\/j.celrep.2016.09.079","article-title":"A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia","volume":"17","author":"Tzelepis","year":"2016","journal-title":"Cell. Rep."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1056\/NEJMoa1005143","article-title":"DNMT3A mutations in acute myeloid leukemia","volume":"363","author":"Ley","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s00277-020-03938-2","article-title":"Updates on DNA methylation modifiers in acute myeloid leukemia","volume":"99","author":"Contieri","year":"2020","journal-title":"Ann. Hematol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3389\/fped.2017.00248","article-title":"Targeting FLT3 Signaling in Childhood Acute Myeloid Leukemia","volume":"5","author":"Sexauer","year":"2017","journal-title":"Front. Pediatr."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1097\/MOH.0000000000000703","article-title":"Chimeric antigen receptor T-cell therapy in acute myeloid leukemia","volume":"29","author":"Koedam","year":"2022","journal-title":"Curr. Opin. Hematol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1182\/blood-2020-142745","article-title":"Preclinical Development of Anti-FLT3 CAR-T Therapy for the Treatment of Acute Myeloid Leukemia","volume":"136","author":"Shrestha","year":"2020","journal-title":"Blood"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"996438","DOI":"10.3389\/fonc.2022.996438","article-title":"Developments and challenges of FLT3 inhibitors in acute myeloid leukemia","volume":"12","author":"Ge","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"6471","DOI":"10.1158\/0008-5472.CAN-15-3569","article-title":"FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia","volume":"76","author":"Traer","year":"2016","journal-title":"Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6215","DOI":"10.1182\/blood-2008-05-158311","article-title":"Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML","volume":"113","author":"Zeng","year":"2009","journal-title":"Blood"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1038\/leu.2012.317","article-title":"Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1\/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia","volume":"27","author":"Wakita","year":"2013","journal-title":"Leukemia"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"32536","DOI":"10.18632\/oncotarget.15812","article-title":"Immunotherapeutic target expression on breast tumors can be amplified by hormone receptor antagonism: A novel strategy for enhancing efficacy of targeted immunotherapy","volume":"8","author":"Jaini","year":"2017","journal-title":"Oncotarget"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.3324\/haematol.2018.208751","article-title":"Chimeric antigen receptor T-cell therapy for acute myeloid leukemia: How close to reality?","volume":"104","author":"Cummins","year":"2019","journal-title":"Haematologica"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.ymthe.2020.06.022","article-title":"Allogeneic FLT3 CAR T Cells with an Off-Switch Exhibit Potent Activity against AML and Can Be Depleted to Expedite Bone Marrow Recovery","volume":"28","author":"Sommer","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Vishwasrao, P., Li, G., Boucher, J.C., Smith, D.L., and Hui, S.K. (2022). Emerging CAR T Cell Strategies for the Treatment of AML. Cancers, 14.","DOI":"10.3390\/cancers14051241"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/bjh.18326","article-title":"Enhanced stimulation of antigen-specific immune responses against nucleophosmin 1 mutated acute myeloid leukaemia by an anti-programmed death 1 antibody","volume":"198","author":"Greiner","year":"2022","journal-title":"Br. J. Haematol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Guinn, B.A., Schuler, P.J., Schrezenmeier, H., Hofmann, S., Weiss, J., Bulach, C., G\u00f6tz, M., and Greiner, J. (2023). A combination of the immunotherapeutic drug anti-programmed death 1 with lenalidomide enhances specific T cell immune responses against acute myeloid leukemia cells. Int. J. Med. Sci., 24.","DOI":"10.3390\/ijms24119285"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9667\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:47:50Z","timestamp":1760125670000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9667"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,2]]},"references-count":117,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24119667"],"URL":"https:\/\/doi.org\/10.3390\/ijms24119667","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,6,2]]}}}