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Polymorphisms in the MLL breakpoint cluster region (BCR)

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Abstract

The MLL gene is involved in many chromosomal translocations leading to both acute myeloid and lymphoid leukemia. Some patients treated for primary malignancies with chemotherapeutic agents that inhibit DNA topoisomerase II (topo II) develop treatment-related leukemia (t-AML) caused by MLL gene rearrangement. Whether these patients are unusually susceptible to anti-topo II drugs, or whether this is a random adverse event is unknown. To discover genetic polymorphisms that may predispose patients to t-AML development, we sequenced the 8.3-kb MLL breakpoint cluster region (BCR) from 22 patients who had been treated with topo II inhibitors and who developed t-AML and from 37 patients who did not, and from eight infants and 20 normal individuals. Four polymorphic sites within Alu repetitive elements were identified; three affected the length of poly-A tracts and one altered the size of a trinucleotide repeat. The three poly-A tract polymorphisms occurred with equal frequency in leukemic patients and controls and hence are not predictors of risk. The trinucleotide GAA repeat has three alleles: (GAA)4, (GAA)5, and (GAA)6. The (GAA)6 allele is very rare. The adult t-AML patients are almost exclusively (GAA)4/5 heterozygotes (83%), whereas the normal population is only 55% (GAA)4/5 heterozygotic and is represented equally by (GAA)4 and (GAA)5 homozygotes (20% each). Only certain trends could be established because of the small sample size of these leukemic groups. Whereas adult t-AML patients are more likely to be (GAA)4/5 heterozygotes, this is not statistically significant, and this polymorphism within the MLL BCR has only a suggestive association with t-AML development.

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Acknowledgements

We are grateful to and thank Dr. Cheng Cheng from the Department of Biostatistics at St. Jude Children's Research Hospital for his statistical help and expertise. We thank Dr. Michelle LeBeau at the University of Chicago for kindly providing the DNA samples from the normal individuals. We thank Paul Gardner at the Howard Hughes Medical Institute of the University of Chicago for his assistance in DNA primer preparation and sequencing analysis. D.E.B. was funded by a postdoctoral research fellowship from the Leukemia Research Foundation. D.E.B., L.L.S., R.L., M.V.R., N.Z.L., R.S, P.S., and J.D.R were supported by the PAAR grant (no. U01GM61393-02) from the NIH. R.S., P.S., and J.D.R. were supported by the Harold and Leila Y. Mathers Foundation. J.D.R. also received support from NIH (grant no. CA84405) and The Spastic Paralysis Foundation of the Illinois-Eastern Iowa District of Kiwanis International.

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  1. Deborah R. Echlin-Bell

    Present address: Markey Cancer Center, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA

  2. Pamela L. Strissel

    Present address: Frauenklinik, University of Erlangen-Nuernberg, Universitatsstrasse 21–23, 91054, Erlangen, Germany

  3. Reiner Strick

    Present address: Frauenklinik, University of Erlangen-Nuernberg, Universitatsstrasse 21–23, 91054, Erlangen, Germany

Authors and Affiliations

  1. Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA

    Deborah R. Echlin-Bell, Lydia L. Smith, Loretta Li, Pamela L. Strissel, Reiner Strick, Vandana Gupta, Jhula Banerjee, Richard Larson & Janet D. Rowley

  2. St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN 38105, USA

    Mary V. Relling & Susan C. Raimondi

  3. Department of Pediatrics, University of Tokyo, 113–8655, Tokyo, Japan

    Yasuhide Hayashi & Tomohiko Taki

  4. Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153, USA

    Nancy Zeleznik-Le

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Echlin-Bell, D.R., Smith, L.L., Li, L. et al. Polymorphisms in the MLL breakpoint cluster region (BCR). Hum Genet 113, 80–91 (2003). https://doi.org/10.1007/s00439-003-0936-2

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