title: VH gene mutation status and cellular drug resistance in chronic lymphocytic leukaemia.
abstract: OBJECTIVE
  B-cell chronic lymphocytic leukaemia (B-CLL) can be divided into two clinical entities based on the immunoglobulin variable heavy chain (VH) gene mutation status, as cases with unmutated VH genes display a more aggressive disease with shorter survival time than mutated cases. The aim of this study was to investigate whether differences in cellular drug resistance could give an explanation for these divergent clinical courses.
  
  
  METHODS
  The VH gene mutation status was analysed in patients with previously untreated B-CLL using VH gene family-specific PCR amplification and nucleotide sequencing. In vitro sensitivity to cytarabine, fludarabine, cladribine, doxorubicin, idarubicin, vincristine, cyclophosphamide, melphalan and prednisolone was assessed using the non-clonogenic in vitro assay, fluorometric microculture cytotoxicity assay.
  
  
  RESULTS
  The VH genes and in vitro drug resistance were successfully analysed in 46 cases, revealing that 25 (54%) cases showed unmutated and 21 (46%) cases mutated VH genes. Interestingly, the unmutated group generally tended to be more chemosensitive than the mutated group with significant differences for cytarabine and prednisolone (P < or = 0.01).
  
  
  CONCLUSIONS
  The propensity of inferior drug response in mutated B-CLL may reflect a more differentiated disease than in unmutated B-CLL. We conclude that the difference in prognosis between B-CLL cases with unmutated and mutated VH genes could not be explained by difference in cellular drug resistance.
authors.affiliation: Department of Internal Medicine, Uppsala University, Uppsala, Sweden. anna.aleskog@medsci.uu.se
authors.forename: Anna
authors.initials: A
authors.lastname: Aleskog
authors.forename: Gerard
authors.initials: G
authors.lastname: Tobin
authors.forename: Anna
authors.initials: A
authors.lastname: Laurell
authors.forename: Ulf
authors.initials: U
authors.lastname: Thunberg
authors.forename: Elin
authors.initials: E
authors.lastname: Lindhagen
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
authors.forename: Kenneth
authors.initials: K
authors.lastname: Nilsson
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.forename: Christer
authors.initials: C
authors.lastname: Sundström
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor / Q000187:drug effects; D017338:Cladribine / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015993:Life Tables; D008558:Melphalan / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology; D016019:Survival Analysis; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D003561:Cytarabine; D017338:Cladribine; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan; D015255:Idarubicin