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

Elife. 2016 Nov 23:5: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.

Keywords: Flt3 Internal tandem duplication; acute myeloid leukemia; cancer biology; developmental biology; hematopoietic stem cell; mouse; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Age of Onset
  • Animals
  • Animals, Newborn
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Fetal Stem Cells / cytology
  • Fetal Stem Cells / metabolism*
  • Fetus
  • Gene Expression Regulation, Leukemic*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • fms-Like Tyrosine Kinase 3 / genetics*
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Runx1 protein, mouse
  • STAT5 Transcription Factor
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3