title: Monitoring dendritic cell and cytokine biomarkers during remission prior to relapse in patients with FLT3-ITD acute myeloid leukemia.
abstract: Relapse occurs frequently after treatment of acute myeloid leukemia (AML) patients with the FMS-like tyrosine kinase 3-internal tandem duplication (ITD) mutation. The availability of immunologic biomarkers to predict patients at high risk could allow clinicians to accelerate alternative treatments such as stem cell transplantation, immunotherapy, or novel drugs. We have previously reported that first diagnostic (FD) ITD(+) AML showed immunophenotypic and functional characteristics of arrested dendritic cell (DC) precursors. In this study, we show that the high frequency of precursor DCs in 16 FD ITD(+) AML samples (Lin(-)/HLA-DR(+)/CD11c(+)/CD123(+)) was associated with a lack of terminal DCs (myeloid DCs: BDCA-1(+) or BDCA-3(+); plasmacytoid DC: BDCA-2(+)). We further evaluated prospectively the peripheral blood complete remission (CR) samples obtained from 11 ITD(+) AML patients after chemotherapy regarding the frequency of DCs and their pattern of cytokine production. Whereas the aberrant frequencies of precursor and terminal plasmacytoid DCs resolved during remission, the myeloid DC compartment did not fully recover. For an available cohort of patients (n = 4) who could be monitored over a period of >15 months after FD, we identified IL-10, TNF-α, IL-6, and IL-1β as cytokines produced by the CR samples at high levels a few months prior to relapse. Cell-free supernatant of an FD ITD(+) AML sample stimulated monocytes obtained from two healthy donors to secrete IL-10, TNF-α, IL-6, and IL-1β. Thus, we hypothesize that ITD(+) AML minimal residual disease can act directly as dysfunctional antigen-presenting cells or indirectly by production of factors that convert monocytes into myeloid-derived suppressor cells secreting cytokines that promote immune evasion. Monitoring these immunologic biomarkers could improve prediction of relapse.
authors.affiliation: Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), OE 6860, Carl-Neuberg Strasse 1, Hannover, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Rickmann
authors.forename: Laura
authors.initials: L
authors.lastname: Macke
authors.forename: Bala Sai
authors.initials: BS
authors.lastname: Sundarasetty
authors.forename: Kathrin
authors.initials: K
authors.lastname: Stamer
authors.forename: Constanca
authors.initials: C
authors.lastname: Figueiredo
authors.forename: Rainer
authors.initials: R
authors.lastname: Blasczyk
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.forename: Juergen
authors.initials: J
authors.lastname: Krauter
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; D000943:Antigens, Differentiation / Q000032:analysis*; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000097:blood* / Q000378:metabolism; D003713:Dendritic Cells / Q000737:chemistry / Q000473:pathology*; D005260:Female; D016162:Genes, Wilms Tumor; D006801:Humans; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D022423:Myeloid Cells / Q000473:pathology; D018365:Neoplasm, Residual; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000943:Antigens, Differentiation; D015415:Biomarkers; D017077:Culture Media, Conditioned; D016207:Cytokines; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3