Cellular carcinogenesis in preleukemic conditions:drivers and defenses

• Published in: FUKUSHIMA JOURNAL OF MEDICAL SCIENCE Vol. 70; no. 1; pp. 11 - 24
• Main Authors: Ueda, Koki, Ikeda, Kazuhiko
• Format: Journal Article
• Language: English
• Published: Japan THE FUKUSHIMA SOCIETY OF MEDICAL SCIENCE 01.01.2024; The Fukushima Society of Medical Science
• Subjects: acute myeloid leukemia; Animals; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; HMGA2; leukemia stem cell; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; MDMX; Mice; Mutation; myeloproliferative neoplasms; preleukemia; Preleukemia - genetics; Preleukemia - pathology; Review; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; myeloproliferative neoplasms; HMGA2; leukemia stem cell; preleukemia; acute myeloid leukemia; MDMX
• ISSN: 0016-2590; 2185-4610
• DOI: 10.5387/fms.2023-17

Acute myeloid leukemia (AML) arises from preleukemic conditions. We have investigated the pathogenesis of typical preleukemia, myeloproliferative neoplasms, and clonal hematopoiesis. Hematopoietic stem cells in both preleukemic conditions harbor recurrent driver mutations; additional mutation provokes further malignant transformation, leading to AML onset. Although genetic alterations are defined as the main cause of malignant transformation, non-genetic factors are also involved in disease progression. In this review, we focus on a non-histone chromatin protein, high mobility group AT-hook2 (HMGA2), and a physiological p53 inhibitor, murine double minute X (MDMX). HMGA2 is mainly overexpressed by dysregulation of microRNAs or mutations in polycomb components, and provokes expansion of preleukemic clones through stem cell signature disruption. MDMX is overexpressed by altered splicing balance in myeloid malignancies. MDMX induces leukemic transformation from preleukemia via suppression of p53 and p53-independent activation of WNT/β-catenin signaling. We also discuss how these non-genetic factors can be targeted for leukemia prevention therapy.