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

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 dis...

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Autores principales:	Hamid Bolouri, Rhonda Ries, Laura Pardo, Tiffany Hylkema, Wanding Zhou, Jenny L. Smith, Amanda Leonti, Michael Loken, Jason E. Farrar, Timothy J. Triche, Soheil Meshinchi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d13c5f80eaca472491942928dac038df
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spelling	oai:doaj.org-article:d13c5f80eaca472491942928dac038df2021-11-25T06:19:44ZA B-cell developmental gene regulatory network is activated in infant AML1932-6203https://doaj.org/article/d13c5f80eaca472491942928dac038df2021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601427/?tool=EBIhttps://doaj.org/toc/1932-6203Infant 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.Hamid BolouriRhonda RiesLaura PardoTiffany HylkemaWanding ZhouJenny L. SmithAmanda LeontiMichael LokenJason E. FarrarTimothy J. TricheSoheil MeshinchiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hamid Bolouri Rhonda Ries Laura Pardo Tiffany Hylkema Wanding Zhou Jenny L. Smith Amanda Leonti Michael Loken Jason E. Farrar Timothy J. Triche Soheil Meshinchi A B-cell developmental gene regulatory network is activated in infant AML
description	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.
format	article
author	Hamid Bolouri Rhonda Ries Laura Pardo Tiffany Hylkema Wanding Zhou Jenny L. Smith Amanda Leonti Michael Loken Jason E. Farrar Timothy J. Triche Soheil Meshinchi
author_facet	Hamid Bolouri Rhonda Ries Laura Pardo Tiffany Hylkema Wanding Zhou Jenny L. Smith Amanda Leonti Michael Loken Jason E. Farrar Timothy J. Triche Soheil Meshinchi
author_sort	Hamid Bolouri
title	A B-cell developmental gene regulatory network is activated in infant AML
title_short	A B-cell developmental gene regulatory network is activated in infant AML
title_full	A B-cell developmental gene regulatory network is activated in infant AML
title_fullStr	A B-cell developmental gene regulatory network is activated in infant AML
title_full_unstemmed	A B-cell developmental gene regulatory network is activated in infant AML
title_sort	b-cell developmental gene regulatory network is activated in infant aml
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/d13c5f80eaca472491942928dac038df
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A B-cell developmental gene regulatory network is activated in infant AML

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