Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations

The FLT3 Internal Tandem Duplication (FLT3ITD) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show that Flt3ITD and cooperating Flt3ITD/Runx1 mutations cause hematopoietic stem cell depletion and myeloid p...

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Main Authors: Shaina N Porter, Andrew S Cluster, Wei Yang, Kelsey A Busken, Riddhi M Patel, Jiyeon Ryoo, Jeffrey A Magee
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2016-11-01
Series:eLife
Subjects:
Online Access:https://elifesciences.org/articles/18882
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spelling doaj-6f6798c6398a49acb152235dcdfef0fd2021-05-05T00:42:47ZengeLife Sciences Publications LtdeLife2050-084X2016-11-01510.7554/eLife.18882Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutationsShaina N Porter0Andrew S Cluster1Wei Yang2Kelsey A Busken3Riddhi M Patel4Jiyeon Ryoo5Jeffrey A Magee6https://orcid.org/0000-0002-0766-4200Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United StatesDivision of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United StatesDepartment of Genetics, Washington University School of Medicine, St. Louis, United StatesDivision of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United StatesDivision of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United StatesDivision of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United StatesDivision of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States; Department of Genetics, Washington University School of Medicine, St. Louis, United StatesThe FLT3 Internal Tandem Duplication (FLT3ITD) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show that Flt3ITD and cooperating Flt3ITD/Runx1 mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3ITD simultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively. While FLT3ITD can activate STAT5 signal transduction prior to birth, this signaling does not alter gene expression until hematopoietic progenitors transition from fetal to adult transcriptional states. Cooperative interactions between Flt3ITD and Runx1 mutations are also blunted in fetal/neonatal progenitors. Fetal/neonatal progenitors may therefore be protected from leukemic transformation because they are not competent to express FLT3ITD target genes. Changes in the transcriptional states of developing hematopoietic progenitors may generally shape the mutation spectra of human leukemias.https://elifesciences.org/articles/18882hematopoietic stem cellFlt3 Internal tandem duplicationacute myeloid leukemia
collection DOAJ
language English
format Article
sources DOAJ
author Shaina N Porter
Andrew S Cluster
Wei Yang
Kelsey A Busken
Riddhi M Patel
Jiyeon Ryoo
Jeffrey A Magee
spellingShingle Shaina N Porter
Andrew S Cluster
Wei Yang
Kelsey A Busken
Riddhi M Patel
Jiyeon Ryoo
Jeffrey A Magee
Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
eLife
hematopoietic stem cell
Flt3 Internal tandem duplication
acute myeloid leukemia
author_facet Shaina N Porter
Andrew S Cluster
Wei Yang
Kelsey A Busken
Riddhi M Patel
Jiyeon Ryoo
Jeffrey A Magee
author_sort Shaina N Porter
title Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
title_short Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
title_full Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
title_fullStr Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
title_full_unstemmed Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
title_sort fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to flt3-itd mutations
publisher eLife Sciences Publications Ltd
series eLife
issn 2050-084X
publishDate 2016-11-01
description The FLT3 Internal Tandem Duplication (FLT3ITD) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show that Flt3ITD and cooperating Flt3ITD/Runx1 mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3ITD simultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively. While FLT3ITD can activate STAT5 signal transduction prior to birth, this signaling does not alter gene expression until hematopoietic progenitors transition from fetal to adult transcriptional states. Cooperative interactions between Flt3ITD and Runx1 mutations are also blunted in fetal/neonatal progenitors. Fetal/neonatal progenitors may therefore be protected from leukemic transformation because they are not competent to express FLT3ITD target genes. Changes in the transcriptional states of developing hematopoietic progenitors may generally shape the mutation spectra of human leukemias.
topic hematopoietic stem cell
Flt3 Internal tandem duplication
acute myeloid leukemia
url https://elifesciences.org/articles/18882
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