title: Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.
abstract: 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.
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, NY 10016 Department of Medicine, New York University Langone Medical Center, New York, NY 10016 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Lau
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Nish
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz 55131, Germany.
authors.forename: Nir
authors.initials: N
authors.lastname: Yogev
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz 55131, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, NY 10016 Department of Medicine, New York University Langone Medical Center, New York, NY 10016 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032 Boris.Reizis@nyumc.org.
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019070:Cell Lineage; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic; D006706:Homeostasis; D007938:Leukemia / Q000235:genetics* / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D008565:Membrane Proteins; C084881:flt3 ligand protein