{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T05:42:15Z","timestamp":1772257335386,"version":"3.50.1"},"reference-count":139,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The search for new therapeutic principles is essential for treating relapsed\/refractory (r\/r) acute myeloid leukemia (AML). Novel principles include genome-agnostic differentiation induction, controlling AML-triggering inflammation, potentiating the immune response and \u2018normalizing\u2019 AML metabolism. This review summarizes data from a phase I study (10 patients, pts) and three case reports reporting 7 pts on the treatment of r\/r AML by reprogramming AML hallmarks using APA, low-dose azacitidine, pioglitazone (PPAR\u03b1\/\u03b3 agonist) and all-trans retinoic acid. APA reprograms the r\/r AML phenotype in patients with clinically and molecularly\/genetically unfavorable risk profiles (17 pts, 16 refractory, one relapsed) in a genome-agnostic manner, restoring the plasticity of AML hallmarks, thereby improving immune surveillance, attenuating inflammation-triggered promotion of AML and distant microbial inflammation (healing of fungal pneumonia during induction of complete remission (CR) with APA), while normalizing leukemia metabolism (restoring phagocytosis and ROS production in leukemic neutrophils). APA induces CR in 10 pts (59%), with only modest hematotoxicity following CR induction. This allows treatment to be carried out in an outpatient setting, including for elderly and comorbid patients. Triple transcriptional modulation, facilitated by epigenetic modelling with azacitidine, targets reprogramming of non-oncogene addiction networks in AML, re-establishing functionally active, closely interrelated myeloid hallmarks and AML cell death genome-agnostically.<\/jats:p>","DOI":"10.3390\/ijms27021067","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:59:54Z","timestamp":1769003994000},"page":"1067","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genome Agnostic Reprogramming of Acute Myelocytic Leukemia Hallmarks by Targeting Non-Oncogene Addictions with Azacitidine Plus Pioglitazone and All-Trans Retinoic Acid"],"prefix":"10.3390","volume":"27","author":[{"given":"Dennis Christoph","family":"Harrer","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, DE-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5252-287X","authenticated-orcid":false,"given":"Florian","family":"L\u00fcke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, DE-93053 Regensburg, Germany"},{"name":"Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, DE-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8781-8187","authenticated-orcid":false,"given":"Tobias","family":"Pukrop","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, DE-93053 Regensburg, Germany"},{"name":"Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, DE-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1821-7887","authenticated-orcid":false,"given":"Albrecht","family":"Reichle","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, DE-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8790-4584","authenticated-orcid":false,"given":"Daniel","family":"Heudobler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, DE-93053 Regensburg, Germany"},{"name":"Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, DE-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1200\/JCO.2017.77.6112","article-title":"CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients with Newly Diagnosed Secondary Acute Myeloid Leukemia","volume":"36","author":"Lancet","year":"2018","journal-title":"J. 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