title: Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood.
abstract: Chronic lymphocytic leukemia (CLL) is a progressive malignancy of mature B-cells that involves the peripheral blood (PB), lymph nodes (LNs) and bone marrow (BM). Although the majority of CLL cells are in a resting state, small populations of proliferating cells exist; however, the anatomical site of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of 'newly born' cells would be highest in the LNs. Using a deuterium oxide (2H) in vivo labeling method in which patients consumed deuterated (heavy) water (2H2O), we determined CLL cell kinetics in concurrently obtained samples from LN, PB and BM. The LN was identified as the anatomical site harboring the largest fraction of newly born cells, compared to PB and BM. In fact, the calculated birth rate in the LN reached as high a 3.3% of the clone per day. Subdivision of the bulk CLL population by flow cytometry identified the subpopulation with the CXCR4dimCD5brightphenotype as containing the highest proportion of newly born cells within each compartment, including the LN, identifying this subclonal population as an important target for novel treatment approaches.
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.|Department of Medicine, Uniformed Services University, Bethesda, MD.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Herndon
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY.
authors.forename: Shih-Shih
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Nakhle S
authors.initials: NS
authors.lastname: Saba
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Janet
authors.initials: J
authors.lastname: Valdez
authors.affiliation: KineMed Inc., Emeryville, CA.
authors.forename: Claire
authors.initials: C
authors.lastname: Emson
authors.affiliation: KineMed Inc., Emeryville, CA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gatmaitan
authors.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Pharmacy, National Institutes of Health Clinical Center, Bethesda, MD.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hughes
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Clare
authors.initials: C
authors.lastname: Sun
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Arthur
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Constance M
authors.initials: CM
authors.lastname: Yuan
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Carsten U
authors.initials: CU
authors.lastname: Niemann
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Marti
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Georg
authors.initials: G
authors.lastname: Aue
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Susan
authors.initials: S
authors.lastname: Soto
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Mohammed Z H
authors.initials: MZH
authors.lastname: Farooqui
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Sarah E M
authors.initials: SEM
authors.lastname: Herman
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY.|Departments of Medicine and Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Hematology Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000368:Aged; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured