Skip to main content
SpringerLink
Log in

Genetic Abnormalities and Drug Resistance in Acute Lymphoblastic Leukemia

  • Chapter
Drug Resistance in Leukemia and Lymphoma III

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 457))

Abstract

Recent advances in cytogenetics and molecular genetics have made it possible to identify an array of genomic abnormalities with prognostic and therapeutic significance. Hyperdiploidy >50 chromosomes and ETV6-CBFA2 fusions have been used to identify low-risk cases, and BCR-ABL and MLL-AF4 to define high-risk leukemias. Despite their clinical utility, the risk classification system based on these findings lack absolute precision and should be complemented with other variables, the most important of which is the early blast cell response to remission induction therapy. Studies of tumor suppressor genes and proto-oncogenes in the BCL2 family genes may unravel the mechanisms of leukemia cell progression and the development of drug resistance, leading to innovative therapies.

As the cure rates for childhood acute lymphoblastic leukemia (ALL) approach 80%, precise methods of risk assessment are needed to permit better selection of treatment that is neither excessive nor inadequate for individual patients. Because one or more genetic abnormalities underlie every case of leukemia, a risk assignment system based on primary genetic abnormalities has great intuitive appeal. Even though over 90% of childhood ALL cases can be readily classified according to numerical or gross structural chromosomal abnormalities, molecular analyses are essential to identify therapeutically relevant, submicroscopic genetic lesions not visible by karyotyping.2 This review focuses mainly on recent advances in genetic studies that have contributed to therapeutic advances or that hold promise for the future.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Pui, C.-H., Mahmoud, H.H., Rivera, G.K., Hancock, M.L., Sandlund, J.T., Behm, F.G., et al. Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood, 92 411–415.

    Google Scholar 

  2. Pui, C.-H. (1997) Acute lymphoblastic leukemia. Pediatr Clin North Am, 44, 831–846.

    Article  PubMed  CAS  Google Scholar 

  3. Kaspers, G.J.L., Smets, L.A., Pieters, R., Van Zantwijk, C.H., Van Wering, E.R., and Veerman, A.J.P. (1995) Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: Results of an in vitro study. Blood, 85, 751–756.

    PubMed  CAS  Google Scholar 

  4. Synold, T.W., Relling, M.V., Boyett, J.M., Rivera, G.K., Sandlund, J.T., Mahmoud, H., et al. (1994) Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest, 94, 1996–2001.

    Article  PubMed  CAS  Google Scholar 

  5. Kumagai, M., Manabe, A., Pui, C.-H., Behm, F.G., Raimondi, S.C., Hancock, M.L., et al. (1996) Stroma-supported culture of childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome. J Clin Invest, 97, 755–760.

    Article  PubMed  CAS  Google Scholar 

  6. Harris, M.B., Shuster, J.J., Carroll, A., Look, A.T., Borowitz, M.J., Crist, W.M., et al. (1992), Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: A pediatric oncology group study. Blood, 79, 3316–3324.

    PubMed  CAS  Google Scholar 

  7. Raimondi. S.C., Pui, C.-H., Hancock, M.L., Behm, F.G., Filatov, L., and Rivera, G.K. (1996) Heterogeneity of hyperdiploid (51–67) childhood acute lymphoblastic leukemia. Leukemia, 10, 213–224.

    PubMed  CAS  Google Scholar 

  8. Raimondi, S.C., Shurtleff, S.A., Downing, J.R., Rubnitz, J., Mathew, S., Hancock, M., et al. (1997) 12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia. Blood, 90, 4559–4566.

    PubMed  CAS  Google Scholar 

  9. McLean, T.W., Ringold, S., Neuberg, D., Stegmaier, K., Tantravahi, R., Ritz, J., et al. (1996) TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood, 11, 4252–4258.

    Google Scholar 

  10. Rubnitz, J.E., Behm, F.G., Pui, C.-H., Evans, W.E., Relling, M.V., Raimondi, S.C., et al. (1997) Genetic studies of childhood acute lymphoblastic leukemia with emphasis on p16, MLL, and ETV6 gene abnormalities: results of St. Jude Total Therapy Study XII. Leukemia, 11, 1201–1206.

    Article  PubMed  CAS  Google Scholar 

  11. Borkhardt, A., Cazzaniga, G., Viehmann, S., Valsecchi, M.G., Ludwig, W. D., Burci, L., et al. (1997) Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Blood, 90, 571–577.

    PubMed  CAS  Google Scholar 

  12. Baruchel, A., Cayuela, J.M., Ballerini, P., Landman-Parker, J., Cezard, V, Firat, H., et al. (1997) The majority of myeloid-antigen positive (My+) childhood B-cell precursor acute lymphoblastic leukemias express TEL-AML1 fusion transcripts. Br J Hematol, 99, 101–106.

    Article  CAS  Google Scholar 

  13. Rubnitz, J.E., Downing, J.R., Pui, C-H., Shurtleff, S.A., Raimondi, S.C., Evans, W.E., et al. (1997) TEL gene rearrangement in acute lymphoblastic leukemia: A new genetic marker with prognostic significance. J Clin Oncol, 15, 1150–1157.

    PubMed  CAS  Google Scholar 

  14. Rubnitz, J.E., Shuster, J., Land, V.J., Link, M.P., Pullen, J., Camitta, B.M., et al. (1997) Case-control study suggests a favorable impact of TEL rearrangement in patients with B-lineage acute lymphoblastic leukemia treated with antimetabolite-based therapy: A pediatric oncology group study. Blood, 89, 1143–1146.

    PubMed  CAS  Google Scholar 

  15. Whitehead, W.M., Payment, C., Vuchich, M-J., Cooley, L., Lauer, S.J., Mahoney, D.H., et al. (1998) The TEL-AML1 translocation and methotrexate polyglutamate (MTXPG) levels in childhood B-progenitor cell acute lymphoblastic leukemia (pro-B ALL): a pediatric oncology group study. Proc AACR, 39, 329.

    Google Scholar 

  16. Nakao, M., Yokota, S., Horiike, S., Taniwaki, M., Kashima, K., Sonoda, Y, et al. (1996) Detection and quantification of TEL/AML1 fusion transcripts by polymerase chain reaction in childhood acute lymphoblastic leukemia. Leukemia, 10, 1463–1470.

    PubMed  CAS  Google Scholar 

  17. Lanza, C., Volpe, G., Basso, G., Gottardi, E., Barisone, E., Spinelli, M., et al. (1997) Outcome and lineage involvement in t(12;21) childhood acute lymphoblastic leukaemia. Br J Haematol, 97, 460–462.

    Article  PubMed  CAS  Google Scholar 

  18. Harbott, J., Viehmann, S., Borkhardt, A., Henze, G., and Lampert, F. (1997) Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood, 12, 4933–4937.

    Google Scholar 

  19. Seeger, K., Adams, H-P., Buchwald, D., Beyermann, B., Kremens, B., Niemeyer, C., et al. (1998) TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. Blood, 91, 1716–1722.

    PubMed  CAS  Google Scholar 

  20. Schrappe, M., Aricò, M., Harbott, J., Biondi, A., Zimmermann, M., Conter, V., et al. (1998) Ph+ childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood, 92, 2730–2741.

    PubMed  CAS  Google Scholar 

  21. Ribeiro, R. C., Broniscer, A., Rivera, G.K., Hancock, M.L., Raimondi, S.C., Sandlund, J.T., et al. (1997) Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts. Leukemia, 11, 1493–1496.

    Article  PubMed  CAS  Google Scholar 

  22. Behm, F.G., Raimondi, S.C., Frestedt, J.L., Liu, Q., Crist, W.M., Downing, J.R., et al. (1996) Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age. Blood, 87, 2870–2877.

    PubMed  CAS  Google Scholar 

  23. Pui, C.-H., Frankel, L.S., Carroll, A.J., Raimondi, S.C., Shuster, J.J., Head, D.R., et al. (1991) Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11) (q21;q23): A collaborative study of 40 cases. Blood, 77, 440–447.

    PubMed  CAS  Google Scholar 

  24. Chen, C-S., Sorensen, P.H.B., Domer, P.H., Reaman, G.H., Korsmeyer, S.J., Heerema, N.A., et al. (1993) Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood, 81, 2386–2393.

    PubMed  CAS  Google Scholar 

  25. Pui, C.-H., Behm, F.G., Downing, J.R., Hancock, M.L., Shurtleff, S.A., Ribeiro, R.C., et al. (1994) 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. J Clin Oncol, 12, 909–915.

    PubMed  CAS  Google Scholar 

  26. Rubnitz, J.E., Link, M.P., Shuster, J.J., Carroll, A.J., Hakami, N., Frankel, L.S., et al. (1994) Frequency and prognostic significance of HRX rearranagements in infant acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood, 84, 570–573.

    PubMed  CAS  Google Scholar 

  27. Pieters, R., den Boer, M.L., Durian, M., Janka, G. Schmiegelow, K., Kaspers, G.J.L., et al. (1998) In vitro drug resistance testing in infant acute lymphoblastic leukemia cells — implications for treatment. Leukemia, 12, 1344–1348.

    Article  PubMed  CAS  Google Scholar 

  28. Silverman, L. B., McLean, T.W., Donnelly, M.J., Gilliland, D.G., Gelber, R.D., and Sallan, S.E. (1996) Improved outcome for infants with acute lymphoblastic leukemia (ALL) with intensification of therapy. Blood, 88(Suppl 1), 668a.

    Google Scholar 

  29. Secker-Walker, L.M., Berger, R., Fenaux, P., Lai, J.L., Nelken, B., Garson, M., et al. (1992) Prognostic significance of the balanced t(1;19) and unbalanced der(19)t(1;19) translocations in acute lymphoblastic leukemia. Leukemia, 6, 363–369.

    PubMed  CAS  Google Scholar 

  30. Uckun, F.M., Sensel, M.G., Sather, H.N., Gaynon, P.S., Arthur, D.C., Lange, B.J., et al. (1998) Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children’s Cancer Group. J Clin Onc, 16, 527–535.

    CAS  Google Scholar 

  31. Pui, C.-H., Raimondi, S.C., Hancock, M.L., Rivera, G.K., Ribeiro, R.C., Mahmoud, H.H., et al. (1994) Immunologie, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19)(q23;p13) or its derivative. J Clin Oncol, 12, 2601–2606.

    PubMed  CAS  Google Scholar 

  32. Hsiao, M.H., Yu, A.L., Yeargin, J., Ku, D., and Haas, M. (1994) Monhereditary p53 mutations in T-Cell acute lymphoblastic leukemia are associated with the relapse phase. Blood, 83, 2922–2930.

    PubMed  CAS  Google Scholar 

  33. Diccianni, M.B., Yu, J., Hsiao, M., Mukherjee, S., Shao, L.-E., and Yu, A.L. (1994) Clinical significance of p53 mutations in relapsed T-cell acute lymphoblastic leukemia. Blood, 84, 3105–3112.

    PubMed  CAS  Google Scholar 

  34. Marks, D.I., Kurz, B. W., Link, M.P., Ng, E., Shuster, J.J., Lauer, S.J., et al. (1996) High incidence of potential p53 inactivation in poor outcome childhood acute lymphoblastic leukemia at diagnosis. Blood, 87, 1155–1161.

    PubMed  CAS  Google Scholar 

  35. Marks, D.I., Kurz, B.W., Link, M.P., Ng, E., Shuster, J.J., Lauer, S.J., et al. (1997) Altered expression of p53 and mdm-2 proteins at diagnosis is associated with early treatment failure in childhood acute lymphoblastic leukemia. J Clin Oncol, 15, 1158–1162.

    PubMed  CAS  Google Scholar 

  36. Okuda, T., Shurtleff, S.A., Valentine, M.B., Raimondi, S.C., Head, D.R., Behm, F., et al. (1995) Frequent deletion of p16 INK4a/MTS1 and p15 INK4b/MTS2 in pediatric acute lymphoblastic leukemia. Blood, 85, 2321–2330.

    PubMed  CAS  Google Scholar 

  37. Takeuchi, S., Bartram, C.R., Seriu, T., Miller, C.W., Tobler, A., Janssen, J.W.G., et al. (1995) Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood. Blood, 86, 755–760.

    PubMed  CAS  Google Scholar 

  38. Lolascon, A., Faienza, M.F., Coppola, B., della Ragione, F., Schettini, F., and Biondi, A. (1996) Homozygous deletions of cyclin-dependent kinase inhibitor genes, p16INK4A and p18, in childhood T cell lineage acute lymphoblastic leukemias. Leukemia, 10, 255–260.

    Google Scholar 

  39. Heyman, M., Rasool, O., Brandter, L.B., Liu, Y., Grandér, D., Söderhäll, S., et al. (1996) Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia. J Clin Oncol, 14, 1512–1520.

    PubMed  CAS  Google Scholar 

  40. Zhou, M., Gu, L., Yeager, A.M., and Findley, H.W. (1997) Incidence and clinical significance of CDKN2/MTSl/P16 ink4A and MTS2/P15 ink4B gene deletions in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol, 14, 141–150.

    Article  PubMed  CAS  Google Scholar 

  41. Kees, U.R., Burton, P.R., Lü, C., and Baker, D.L. (1997) Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. Blood, 89, 4161–4166.

    PubMed  CAS  Google Scholar 

  42. Kamijo, T., Zindy, F., Rousel, M.F., Quelle, D.E., Downing, J.R., Ashmun, R.A., et al. (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell, 91, 649–659.

    Article  PubMed  CAS  Google Scholar 

  43. Gardie, B., Cayuela, J-M., Martini, S., and Sigaux, F. (1998) Genomic alterations of the p19ARF encoding exons in T-cell acute lymphoblastic leukemia. Blood, 91, 1016–1020.

    PubMed  CAS  Google Scholar 

  44. Kroemer, G. (1997) The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nature Med, 3, 614–620.

    Article  PubMed  CAS  Google Scholar 

  45. Reed, J.C. (1997) Double identity for proteins of the Bcl-2 family. Nature, 387, 773–776.

    Article  PubMed  CAS  Google Scholar 

  46. Coustan-Smith, E., Kitanaka, A., Pui, C-H., McNinch, L., Evans, W.E., Raimondi, S.C., et al. (1996) Clinical relevance of BCL-2 overexpression in childhood acute lymphoblastic leukemia. Blood, 87, 1140–1146.

    PubMed  CAS  Google Scholar 

  47. Uckun, F.M., Yang, Z., Sather, H., Steinherz, P., Nachman, J., Bostrom, B., et al. (1997) Cellular expression of antiapoptotic BCL-2 oncoprotein in newly diagnosed childhood acute lymphoblastic leukemia: A Children’s Cancer Group study. Blood, 89, 3769–3777.

    PubMed  CAS  Google Scholar 

  48. Findley, H.W., Gu, L., Yeager, A.M., and Zhou, M. (1997) Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia. Blood, 89, 2986–2993.

    PubMed  CAS  Google Scholar 

  49. Salomons, G.S., Brady, H.J.M., Verwijs-Janssen, M., Van Den Berg, J.D., Hart, A.A.M., Van Den Berg, H., et al. (1997) The Baxα:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. Int J Cancer, 71, 959–965.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. St. Jude Children’s Research Hospital and The University of Tennessee, Memphis, Tennessee, USA

    Ching-Hon Pui & William E. Evans

Authors
  1. Ching-Hon Pui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William E. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University Hospital Vrije Universiteit, Amsterdam, The Netherlands

    G. J. L. Kaspers , R. Pieters  & A. J. P. Veerman ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Science+Business Media New York

About this chapter

Cite this chapter

Pui, CH., Evans, W.E. (1999). Genetic Abnormalities and Drug Resistance in Acute Lymphoblastic Leukemia. 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_40

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4811-9_40

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7180-9

  • Online ISBN: 978-1-4615-4811-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation