title: CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL.
abstract: The world of chronic lymphocytic leukemia (CLL) research is awash with prognostic markers. However, very few of the current group play a clearly defined role in the pathology of this disease and even fewer represent a tractable therapeutic target. One such marker that fulfils both of these criteria is the integrin CD49d. This molecule been implicated in the capacity of CLL cells to migrate into lymphoid tissues and there is a CD49d blocking antibody, Natalizumab, currently in clinical trials. Here we carried out the largest multi-centre evaluation of CD49d as a prognostic marker in 652 primary CLL samples. We confirm that CD49d is predictive for time to first treatment (P<0.0001) and overall survival (P<0.0001) and increases the prognostic power of CD38, ZAP-70 and IGHV gene mutation status in concordant cases. Furthermore, CD49d retained independent prognostic significance in multivariate analysis. In contrast to previous studies, we showed no correlation between CD49d expression and in vitro resistance to fludarabine in liquid cultures (P=0.28) but CD49d(hi) cells were significantly more resistant than CD49d(lo) cells when assays were carried out on fibronectin-coated plates (P=0.03). Furthermore, we showed for the first time that the expression of CD49d is strongly associated with expression of the chemokine receptor CXCR4 suggesting a co-ordinated role for these molecules in the trafficking of CLL cells to the lymphoid tissues. Taken together, our data support the introduction of CD49d into routine immunophenotyping panels for CLL and indicate that the therapeutic targeting of this molecule may prove useful in this disease.
authors.affiliation: Medical Research Council (MRC) Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: Aneela
authors.initials: A
authors.lastname: Majid
authors.forename: Thet Thet
authors.initials: TT
authors.lastname: Lin
authors.forename: Giles
authors.initials: G
authors.lastname: Best
authors.forename: Keith
authors.initials: K
authors.lastname: Fishlock
authors.forename: Saman
authors.initials: S
authors.lastname: Hewamana
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Deborah
authors.initials: D
authors.lastname: Yallop
authors.forename: Andrea G S
authors.initials: AG
authors.lastname: Buggins
authors.forename: Simon
authors.initials: S
authors.lastname: Wagner
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Kennedy
authors.forename: Fiona
authors.initials: F
authors.lastname: Miall
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.forename: Stephen
authors.initials: S
authors.lastname: Devereux
authors.forename: David G
authors.initials: DG
authors.lastname: Oscier
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D039441:Integrin alpha4 / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000378:metabolism*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D019718:Receptors, CXCR4; D039441:Integrin alpha4; D051746:ZAP-70 Protein-Tyrosine Kinase; D051997:ADP-ribosyl Cyclase 1; D014740:Vidarabine; C024352:fludarabine