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

Abstract

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.

Data availability

The following data sets were generated
The following previously published data sets were used
    1. Levine RL
    2. Shin A
    (2015) Tet2-/-Flt3ITD and WT stem and progenitor cells
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE57244).

Article and author information

Author details

  1. Shaina N Porter

    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Andrew S. Cluster

    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Wei Yang

    Department of Genetics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kelsey A Busken

    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Riddhi M Patel

    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiyeon A Ryoo

    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeffrey A Magee

    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States
    For correspondence
    Magee_J@kids.wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0766-4200

Funding

U.S. Department of Defense (CA130124)

  • Jeffrey A Magee

St. Baldrick's Foundation (Scholar Award)

  • Jeffrey A Magee

Hyundai Hope On Wheels (Hope Scholar)

  • Jeffrey A Magee

Gabrielle's Angel Foundation for Cancer Research (Medical Research Award)

  • Jeffrey A Magee

Children's Discovery Institute of Washington University and St. Louis Children's Hospital (Faculty Scholar Award)

  • Jeffrey A Magee

Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12-HD076224)

  • Jeffrey A Magee

Eunice Kennedy Shriver National Institute of Child Health and Human Development (5T32HD043010-12)

  • Andrew S. Cluster

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Scott A Armstrong, Harvard University, United States

Ethics

Animal experimentation: All mice were housed in the Department for Comparative Medicine at Washington University. All animals were handled and procedures were performed according to institutional animal care and use committee (IACUC) protocols 20130134 and 20160087. These protocols were approved by the Washington University Committees on the Use and Care of Animals.

Version history

  1. Received: June 16, 2016
  2. Accepted: November 21, 2016
  3. Accepted Manuscript published: November 23, 2016 (version 1)
  4. Version of Record published: December 12, 2016 (version 2)

Copyright

© 2016, Porter et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shaina N Porter
  2. Andrew S. Cluster
  3. Wei Yang
  4. Kelsey A Busken
  5. Riddhi M Patel
  6. Jiyeon A Ryoo
  7. Jeffrey A Magee
(2016)
Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
eLife 5:e18882.
https://doi.org/10.7554/eLife.18882

Share this article

https://doi.org/10.7554/eLife.18882

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