title: Elevated frequencies of leukemic myeloid and plasmacytoid dendritic cells in acute myeloid leukemia with the FLT3 internal tandem duplication.
abstract: Some 30% of acute myeloid leukemia (AML) patients display an internal tandem duplication (ITD) mutation in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3-ITDs are known to drive hematopoietic stem cells towards FLT3 ligand independent growth, but the effects on dendritic cell (DC) differentiation during leukemogenesis are not clear. We compared the frequency of cells with immunophenotype of myeloid DC (mDC: Lin(-), HLA-DR(+), CD11c(+), CD86(+)) and plasmacytoid DC (pDC: Lin(-), HLA-DR(+), CD123(+), CD86(+)) in diagnostic samples of 47 FLT3-ITD(-) and 40 FLT3-ITD(+) AML patients. The majority of ITD(+) AML samples showed high frequencies of mDCs or pDCs, with significantly decreased HLA-DR expression compared with DCs detectable in ITD(-) AML samples. Interestingly, mDCs and pDCs sorted out from ITD(+) AML samples contained the ITD insert revealing their leukemic origin and, upon ex vivo culture with cytokines, they acquired DC morphology. Notably, mDC/pDCs were detectable concurrently with single lineage mDCs and pDCs in all ITD(+) AML (n = 11) and ITD(-) AML (n = 12) samples analyzed for mixed lineage DCs (Lin(-), HLA-DR(+), CD11c(+), CD123(+)). ITD(+) AML mDCs/pDCs could be only partially activated with CD40L and CpG for production of IFN-α, TNF-α, and IL-1α, which may affect the anti-leukemia immune surveillance in the course of disease progression.
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Rickmann
authors.forename: Juergen
authors.initials: J
authors.lastname: Krauter
authors.forename: Kathrin
authors.initials: K
authors.lastname: Stamer
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salguero
authors.forename: Eva
authors.initials: E
authors.lastname: Mischak-Weissinger
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Renata
authors.initials: R
authors.lastname: Stripecke
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002452:Cell Count; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D020440:Gene Duplication / Q000502:physiology; D005787:Gene Frequency; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D020080:Tandem Repeat Sequences / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3