Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses

J Exp Med. 2016 Mar 7;213(3):415-31. doi: 10.1084/jem.20150642. Epub 2016 Feb 22.


A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Lineage
  • Cell Proliferation
  • Dendritic Cells / immunology*
  • Down-Regulation
  • Gene Duplication*
  • Gene Expression Regulation, Leukemic
  • Homeostasis
  • Leukemia / genetics*
  • Leukemia / immunology*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Signal Transduction
  • T-Lymphocytes / immunology*


  • Membrane Proteins
  • flt3 ligand protein