Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia

Abstract

<jats:p>A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them from de novo AML. Over the last decade, molecular techniques have unraveled the complex subclonal architecture of sAML and t-MN. In this review, we compare and contrast biological and clinical features of de novo AML with sAML and t-MN. We discuss the role of genetic mutations, including those involved in RNA splicing, epigenetic modification, tumor suppression, transcription regulation, and cell signaling, in the pathogenesis of secondary leukemia. We also discuss clonal hematopoiesis in otherwise healthy individuals, as well as in the context of another malignancy, and how it challenges the conventional notion of sAML/t-MN. We conclude by summarizing the current and emerging treatment strategies, including allogenic transplant, in these complex scenarios.</jats:p>

Glucocorticoid and Antibiotic Treatment-induced Recapitulated Hematological Remissions in Acute Myeloid Leukemia: Implications for Ligand-dependent Growth and Survival Advantage

“…Acquisition of enhanced self-renewal capacity results from the fused genes such as in recurrent chromosome arrangements and the mutated genes such as in transcription factor signaling pathways responsible for differentiation in certain lineage and certain stage of hematopoietic progenitors. Acquisition of clonal growth advantages results from the fused genes or mutated genes in growth receptors or their signaling pathways [1][2][3].…”

“…It is generally accepted that the constitutionally activated growth factor receptor signaling pathways are responsible for the growth and survival advantage in leukemic stem cells such as the formation of fused genes involving ABL, FGFR1 and PDGFR and mutated genes involving FLT3 and KIT, which result in the autonomous proliferation [1][2][3]. However, there may be another form of activating growth factor receptor signaling pathways in AML, ligand-dependent activation, like mutated genes in the B-cell receptor signaling pathway in lymphoma pathogenesis in which the antigen-dependent growth and survival advantages has been well elucidated [13][14][15][16][17].…”

“…It is the growth and survival advantage that lead to the accumulation and in ltration of a large amount of clonal leukemic cells in the bone marrow, taking up the hematopoietic pool, inhibiting the polyclonal normal hematopoiesis and ultimately resulting in the decreased capacity of producing mature blood cells. Anemia due to the decreased production of red blood cell, spontaneous hemorrhage due to the deceased production of platelet, and infection due to the decreased production of mature white blood cell are the major clinical presentations in AML patients [1][2][3].…”

Type of prior genotoxic insult determines the genomic characteristics of therapy‐related myeloid neoplasms

“…Note, tMN may arise from treatment-induced selection of preexisting clones harboring mutations (i.e., clonal hematopoiesis [CH]), or as a result of de novo mutations in healthy hematopoietic stem cells. 1 A previous study analyzed pre-chemotherapy and postchemotherapy blood and bone marrow samples from patients with tMN, and reported that the exact TP53 mutation found at the diagnosis of tMN was also present years before the diagnosis, prior to their first chemotherapy. 5 A large cross-sectional analysis of 7379 solid tumor patients with CH investigated the factors associated with CH, including smoking and prior therapies.…”

Expression, Regulation and Function of microRNA as Important Players in the Transition of MDS to Secondary AML and Their Cross Talk to RNA-Binding Proteins

“…According to the revised World Health Organization (WHO) classification in 2017, de novo acute myeloid leukemia (AML) and sAML with MDS-related changes are distinct diseases, which significantly differ in terms of their biologic and clinical features [ 3 , 9 ]. In contrast, high risk MDS and sAML share phenotypic and genetic characteristics, including overlapping somatic mutations and chromosomal rearrangement alterations in a variety of genes involved in disease pathogenesis, such as RNA splicing, DNA methylation, ras signaling, and transcriptional regulation [ 10 , 11 , 12 ].…”