1. Cancer Biology
  2. Developmental Biology
Download icon

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

  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  Is a corresponding author
  1. Washington University School of Medicine, United States
Research Article
  • Cited 11
  • Views 1,502
  • Annotations
Cite this article as: eLife 2016;5:e18882 doi: 10.7554/eLife.18882

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.

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.

Reviewing Editor

  1. Scott A Armstrong, Harvard University, United States

Publication 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.

Metrics

  • 1,502
    Page views
  • 347
    Downloads
  • 11
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, PubMed Central, Crossref.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Developmental Biology
    Rediet Zewdu et al.
    Research Article

    Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAFV600E driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. NKX2-1-deficient, BRAFV600E driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.

    1. Cancer Biology
    2. Cell Biology
    Margaret E Torrence et al.
    Research Article Updated

    The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.