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

Authors :
Wanding Zhou
Timothy J. Triche
Rhonda E. Ries
Jenny L. Smith
Amanda R. Leonti
Soheil Meshinchi
Laura Pardo
Michael R. Loken
Jason E. Farrar
Hamid Bolouri
Tiffany A. Hylkema
Source :
PLoS ONE, Vol 16, Iss 11, p e0259197 (2021), PLoS ONE, PLoS ONE, Vol 16, Iss 11 (2021)
Publication Year :
2021
Publisher :
Public Library of Science (PLoS), 2021.

Abstract

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.

Details

Language :
English
ISSN :
19326203
Volume :
16
Issue :
11
Database :
OpenAIRE
Journal :
PLoS ONE
Accession number :
edsair.doi.dedup.....3022a5655740e23fc0b7dcf84b1d6af0