Abstract
The overexpression of the multidrug resistance gene MDR1 has been found to be associated with therapy-resistance in hematological malignancies. Yet the cellular mechanisms underlying this increased expression are completely unknown. Point mutations in the MDR1 promoter have been found in osteogenic sarcoma (Stein et al., Eur J of Cancer, 30A: 1541–1545, 1994). We therefore analyzed DNA from hematological malignancies for MDR1 promoter point mutations. Two pairs of overlapping PCR primers were designed which did not amplify the MDR3 gene. Amplified DNA was screened using single strand conformation polymorphism (SSCP). 139 patients and 93 normal controls were studied. Fifteen patients (11%) were found to have abnormal bands on the SSCP analysis. Of these, 9 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia (CLL), 1 acute lymphocytic leukemia (ALL), and 1 nonHodgkin’s lymphoma (NHL). Sequence analysis revealed that all patients were heterozygous for a point mutation in the promoter (T-C transition at +8). Four normals (4%) were found to be heterozygous for the mutation. Confirmation of the mutation was performed by oligonucleotide probe hybridization. All but two of the AML patients have died due to chemoresistant disease (one is lost to followup). Of the CLL patients, one is alive with progressive disease, and the others have died. Further studies will assess the effect of this mutation on MDR1 gene transcription.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Pastan I, Gottesman M: Multidrug resistance. Ann Rev Med 1991;42:277–286
Simon S, Schindler M: Cell biological mechanisms of multidrug resistance in tumors. Proc Natl Acad Sci USA 91:3497–3504, 1994
Jones P: DNA methylation errors and cancer. Cancer Research 1996;56:2463–2467
Stein U, Walther W, Wunderlich V: Point mutations in the mdr1 promoter of human osteosarcomas are associated with in vitro responsiveness to multidrug resistance relevant drugs. Euro J Cancer 1994;30A: 1541–1545
Chaudhary P, Roninson I: Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 1991;66:85–94
Broxterman H, Lankelman J, Pinedo H, Eekman C, Wahrer D, Ossenkoppele G, Schuurhuis G: Theoretical and practical considerations for the measurement of P-glycoprotein function in acute meyloid leukemia. Leukemia 1997;11:1110–1118
Webb M, Raphael C, Asbahr H, Erber W, Meyer B: The detection of rhodamine 123 drug efflux at low levels of drug resistance. Br J Haematol 1996;93:650–655
Young I: Proof without prejudice: use of Kolgomorov-Smirnov test for the analysis of histograms from flow systems and other sources. J. Histochem Cytochem 1977;25:935–941
Beck W, Grogan T, Williams C, Cordon-Cardo C, Parham D, Kuttesch J, Andreef M, Bates S, Berard C, Boyett J, Brophy N, Broxterman H, Chan H, Dalton W, Dietel M, Fojo A, Gascoyne R, Head D, Houghton P, Srivastava D, Lehnert M, Leith C, Paietta E, Pavelic Z, Rimsza L, Roninson I, Sikic B, Twentyman P, Warnke R, Weinstein R: Methods to detect P-glycoprotein-associated resistance in patients’ tumors: consensus recommendations. Cancer Research 1996;56:3010–3020
Ivy S, Olshevski R, Taylor B, Patel K, Reaman G: Correlation of P-glycoprotein expression and function in childhood acute leukemia,. Blood 1996;88:309–318
Pall G, Spitaler M, Gofman J, Thaler J, Ludescher C: Multidrug resistance in leukemia: a comparison of different diagnostic methods. Leukemia 1997; 11:1067–1072
Rund D, Cohen T, Filon D, Dowling CE, Warren TC, Barak I, Rachmilewitz EA, Kazazian HH, Oppenheim A: Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan. Proc Natl Acad Sci USA 1991;88:310–314
Hayashi K: PCR-SSCP: a simple and sensitive method for detection of mutations in the genomic DNA. PCR Method Applications 1991;1:34–38
Glavac D, Dean M: Optimization of the single-strand conformation polymorphism (SSCP) technique for detection of point mutations. Human Mutation 1993;2:404–414
Ueda K, Pastan I, Gottesman M: Isolation and sequence of the promoter region of the human multi-drug resistance (P-glycoprotein) gene. J Biol Chem 1987;262:17432–17436
Cornwell M, Smith D: SP1 activates the MDR1 promoter through one of two distinct G-rich regions that modulate promoter activity. J Biol Chem 1993;26:19505–19511
Cohen D, Yu L, Rzepka R, Horwitz S: Identification of two nuclear protein binding sites and their role in the regulation of the murine multidrug resistance mdr1a promoter. DNA and Cell Biology 1994;13:641–649
van Groenigen M, Valentijn L, Baas F: Identification of a functional initiator sequence in the human MDR1 promoter. Biochimica Biophysica Acta 1993; 1172:138–146
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Science+Business Media New York
About this chapter
Cite this chapter
Rund, D., Azar, I., Shperling, O. (1999). A Mutation in the Promoter of the Multidrug Resistance Gene (MDR1) in Human Hematological Malignancies may Contribute to the Pathogenesis of Resistant Disease. In: Kaspers, G.J.L., Pieters, R., Veerman, A.J.P. (eds) Drug Resistance in Leukemia and Lymphoma III. Advances in Experimental Medicine and Biology, vol 457. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4811-9_9
Download citation
DOI: https://doi.org/10.1007/978-1-4615-4811-9_9
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7180-9
Online ISBN: 978-1-4615-4811-9
eBook Packages: Springer Book Archive