A B-cell developmental gene regulatory network is activated in infant AML

• Published in: PloS one Vol. 16; no. 11; p. e0259197
• Main Authors: Bolouri, Hamid, Ries, Rhonda, Pardo, Laura, Hylkema, Tiffany, Zhou, Wanding, Smith, Jenny L, Leonti, Amanda, Loken, Michael, Farrar, Jason E, Triche, Jr, Timothy J, Meshinchi, Soheil
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.11.2021; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Age; Age groups; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Babies; Biology and Life Sciences; Cancer; CD19 antigen; CD20 antigen; CD22 antigen; Cell Cycle Proteins - genetics; Children; Deoxyribonucleic acid; Diseases; DNA; DNA Methylation; DNA polymerase; Enzymes; Epigenetics; Fetuses; Gene Regulatory Networks - genetics; Genes; Genetic regulation; Genetic testing; Genomes; Health aspects; Humans; Infant; Infants; Leukemia; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Lymphocytes B; Malignancy; Medical research; Medicine and Health Sciences; MicroRNAs - metabolism; miRNA; mRNA; Mutation; Myeloid leukemia; Patients; Pediatrics; People and Places; Rare diseases; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; Robotics; Software; Trans-Activators - genetics; Transcription Factors - genetics; Translocation; Up-Regulation; United States; United States > US; Grand Rapids Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0259197

Infant Acute Myeloid Leukemia (AML) is a poorly-addressed, heterogeneous malignancy distinguished by surprisingly few mutations per patient but accompanied by myriad age-specific translocations. These characteristics make treatment of infant AML challenging. While infant AML is a relatively rare disease, it has enormous impact on families, and in terms of life-years-lost and life limiting morbidities. To better understand the mechanisms that drive infant AML, we performed integrative analyses of genome-wide mRNA, miRNA, and DNA-methylation data in diagnosis-stage patient samples. Here, we report the activation of an onco-fetal B-cell developmental gene regulatory network in infant AML. AML in infants is genomically distinct from AML in older children/adults in that it has more structural genomic aberrations and fewer mutations. Differential expression analysis of ~1500 pediatric AML samples revealed a large number of infant-specific genes, many of which are associated with B cell development and function. 18 of these genes form a well-studied B-cell gene regulatory network that includes the epigenetic regulators BRD4 and POU2AF1, and their onco-fetal targets LIN28B and IGF2BP3. All four genes are hypo-methylated in infant AML. Moreover, micro-RNA Let7a-2 is expressed in a mutually exclusive manner with its target and regulator LIN28B. These findings suggest infant AML may respond to bromodomain inhibitors and immune therapies targeting CD19, CD20, CD22, and CD79A.