Leukemic and non-leukemic lymphocytes from patients with Li Fraumeni syndrome demonstrate loss of p53 function, Bcl-2 family dysregulation and intrinsic resistance to conventional chemotherapeutic drugs but not flavopiridol.
Li Fraumeni syndrome (LFS) is characterised by a predisposition to the early onset of certain tumors and is associated with germline mutation of the anti-oncogene p53. In this study we analysed the in vitro responses of lymphocytes from two LFS patients to chemotherapeutic drugs in terms of apoptosis induction and the expression of key intracellular proteins that regulate this process. One of the LFS patients also suffered from B-cell chronic lymphocytic leukemia (B-CLL) and hence presented with a light-chain restricted B-cell lymphocytosis while the other patient had entirely normal blood counts. The B-lymphocytes from both LFS patients showed a marked degree of resistance to chlorambucil and fludarabine when compared to age-matched controls but were remarkably sensitive to the novel flavone, flavopiridol. Loss of function of p53 was demonstrated by a failure to induce Bax and p21 protein expression. In addition, altered basal expression patterns of Bcl-2 and Bax, two key regulators of apoptosis, were found in the LFS lymphocytes when compared with controls. These results suggest that LFS lymphocytes carrying a p53 mutation show intrinsic resistance to conventional chemotherapeutic drugs and this is associated with dysregulation of Bcl-2 family proteins. Furthermore, The innate resistance profile was similar in leukemic and non-leukemic lymphocytes and was therefore independent of genetic changes acquired during malignant transformation. Novel agents that induce p53-independent cell killing may be useful not only in the treatment of LFS-associated tumors but also drug resistant tumors in general where p53 and/or Bcl-2 family dysregulation is a feature.
Pepper
Chris
C
Llandough Hospital, Penlan Road, Penarth, Vale of Glamorgan CF64 2XX, Wales, UK. chrisp@llanhaem.demon.co.uk
Thomas
Alun
A
Hoy
Terry
T
Tighe
Jane
J
Culligan
Dominic
D
Fegan
Chris
C
Bentley
Paul
P
D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016864:Li-Fraumeni Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D005419:Flavonoids; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C077990:alvocidib