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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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 |
work_keys_str_mv |
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