title: Differential control of G0 programme in chronic lymphocytic leukaemia: a novel prognostic factor.
abstract: Chronic lymphocytic leukaemia (CLL) is a unique malignancy where quiescent B cells accumulate in the peripheral blood. Since clinical outcomes in CLL are very heterogeneous, it is of utmost importance to correctly assess the disease prognosis in each individual case. Recently, it has been shown that high ZAP-70 [Zeta-chain (T-cell receptor) associated protein kinase (70 kDa)] expression level strongly correlates with lack of IgV(H) mutations and poor prognosis in B-CLL. As CLL malignant cells are arrested in G(0), we investigated whether Dipeptidyl Peptidase 2 (DPP2), a serine protease that plays a key role in keeping cells in the quiescent state, is involved in cell-cycle control in CLL. We have previously shown that specific inhibition of DPP2 results in apoptosis of normal lymphocytes. In this study, cell apoptosis experiments were conducted in 38 patients with B-CLL. Two distinct subsets of B-CLL were identified, susceptible and resistant to DPP2-inhibition-induced apoptosis. If resistant to apoptosis (42.1%), the CLL cells have higher expression of ZAP-70 and exhibit a worse prognosis, such as shorter treatment-free time period. Thus, resistance vs. susceptibility to DPP2-inhibiton induced apoptosis can be employed as a novel prognostic factor in CLL.
authors.affiliation: Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Danilov
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Klein
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Lee
authors.forename: Diana Velez
authors.initials: DV
authors.lastname: Baez
authors.forename: Brigitte T
authors.initials: BT
authors.lastname: Huber
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D002453:Cell Cycle; D016923:Cell Death / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D004151:Dipeptides; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; C477478:PT-100 dipeptide; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II