VH gene mutation status and cellular drug resistance in chronic lymphocytic leukaemia.
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.
Aleskog
Anna
A
Department of Internal Medicine, Uppsala University, Uppsala, Sweden. anna.aleskog@medsci.uu.se
Tobin
Gerard
G
Laurell
Anna
A
Thunberg
Ulf
U
Lindhagen
Elin
E
Roos
Göran
G
Nilsson
Kenneth
K
Nygren
Peter
P
Sundström
Christer
C
Höglund
Martin
M
Larsson
Rolf
R
Rosenquist
Richard
R
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
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