Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinions and Ideas
  • Published:

Riddle: What do aplastic anemia, acute promyelocytic leukemia, and chronic myeloid leukemia have in common?

Leukemia volume 18, pages 1740–1742 (2004)Cite this article

Abstract

Secondary myelodysplastic syndrome (MDS)/acute leukemia frequently evolves from severe aplastic anemia (SAA) following immunosuppressive therapy. Secondary clonal cytogenetic abnormalities have now been reported after noncytotoxic therapy in two additional settings: all trans retinoic acid (ATRA) treatment of acute promyelocytic leukemia (APL) and imatinib for chronic myeloid leukemia (CML). We propose that SAA, APL, CML, and MDS represent different manifestations of generalized insults to the bone marrow. In SAA, the insult to hematopoietic progenitors leads to an immune attack, while in APL, CML, and MDS, it gives rise to the malignant clones. A primary insult to bone marrow could simultaneously lead to several abnormal hematopoietic cell clones, with one dominating and the others present but below the level of detection. Such a ‘field leukemogenic effect’ would be analogous to the ‘field cancerization effect’ described in solid tumors. Nonspecific cytotoxic therapies, including antileukemic chemotherapy and allogeneic transplantation, have broad activity that could inhibit both the overt disease and other undetectable coexistent abnormal clones. In contrast, disease-specific targeted therapy such as immunosuppressive therapy in aplastic anemia, ATRA in APL, or imatinib in CML would have no activity against other abnormal clones, allowing them to expand and become detectable as the dominant clone declines.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Dameshek W . Riddle: What do aplastic anemia, paroxysmal nocutrnal hemoglobinuria (PNH) and ‘hypoplastic’ leukemia have in common? (Editorial). Blood 1967; 30: 251–254.

    CAS  PubMed  Google Scholar 

  2. Young NS . Acquired aplastic anemia. Ann Intern Med 2002; 136: 534–546.

    Article  PubMed  Google Scholar 

  3. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993; 73: 703–711.

    Article  CAS  PubMed  Google Scholar 

  4. Tichelli A, Gratwohl A, Nissen C, Speck B . Late clonal complications in severe aplastic anemia. Leuk Lymphoma 1994; 12: 167–175.

    Article  CAS  PubMed  Google Scholar 

  5. Ohara A, Kojima S, Hamajima N, Tsuchida M, Imashuku S et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997; 90: 1009–1013.

    CAS  PubMed  Google Scholar 

  6. Rosenfeld S, Follmann D, Nunez O, Young NS . Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA 2003; 289: 1130–1135.

    Article  CAS  PubMed  Google Scholar 

  7. Socie G, Henry-Amar M, Bacigalupo A, Hows JM, Tichelli A, Ljungman P et al. Malignant tumors occuring after treatment of aplastic anemia. N Engl J Med 1993; 329: 1152–1157.

    Article  CAS  PubMed  Google Scholar 

  8. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997; 337: 1021–1028.

    Article  CAS  PubMed  Google Scholar 

  9. Latagliata R, Petti MC, Fenu S, Mancini M, Spiriti MA, Breccia M et al. Therapy-related myelodysplastic syndrome–acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem. Blood 2002; 99: 822–824.

    Article  CAS  PubMed  Google Scholar 

  10. Lobe I, Rigal-Huguet F, Vekhoff A, Desablens B, Bordessoule D, Mounier C et al. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience. Leukemia 2003; 17: 1600–1604.

    Article  CAS  PubMed  Google Scholar 

  11. Nowell PC, Hungerford DA . A minute chromosome in human chronic granulocytic leukemia. Science 1960; 132: 1497.

    Google Scholar 

  12. Rowley JD . A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243: 290–293.

    Article  CAS  PubMed  Google Scholar 

  13. Ben-Neriah Y, Daley GQ, Mes-Masson A-M, Witte ON, Baltimore D . The chronic myelogenous leukemia – Specific P210 protein is the product of the bcr-abl hybrid gene. Science 1986; 233: 212–214.

    Article  CAS  PubMed  Google Scholar 

  14. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ et al. Inhibition of the Abl protein–tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 1996; 56: 100–104.

    CAS  PubMed  Google Scholar 

  15. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  PubMed  Google Scholar 

  16. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.

    Article  CAS  PubMed  Google Scholar 

  17. Bumm T, Muller C, Al Ali HK, Krohn K, Shepherd P, Schmidt E et al. Emergence of clonal cytogenetic abnormalities in Ph-cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101: 1941–1949.

    Article  CAS  PubMed  Google Scholar 

  18. O'Dwyer ME, Gatter KM, Loriaux M, Druker BJ, Olson SB, Magenis RE et al. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Leukemia 2003; 17: 481–487.

    Article  CAS  PubMed  Google Scholar 

  19. Medina J, Kantarjian H, Talpaz M, O'Brien S, Garcia-Manero G, Giles F et al. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer 2003; 98: 1905–1911.

    Article  CAS  PubMed  Google Scholar 

  20. Feldman E, Najfeld V, Schuster M, Roboz G, Chadburn A, Silver RT . The emergence of Ph−, trisomy-8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate. Exp Hematol 2003; 31: 702–707.

    Article  CAS  PubMed  Google Scholar 

  21. Fialkow PJ, Martin PJ, Najfeld V, Penfold GK, Jacobson RJ, Hansen JA . Evidence for a multistep pathogenesis of chronic myelogenous leukemia. Blood 1981; 58: 158–163.

    CAS  PubMed  Google Scholar 

  22. Slaughter DP, Southwick HW, Smejkal W . Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: 963–968.

    Article  CAS  PubMed  Google Scholar 

  23. Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH . A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 2003; 63: 1727–1730.

    CAS  PubMed  Google Scholar 

  24. Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS . A severe and consistent deficit in marrow and circulating primitive hematopoietic cells (long-term culture-initiating cells) in acquired aplastic anemia. Blood 1996; 88: 1983–1991.

    CAS  PubMed  Google Scholar 

  25. Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS . Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol 2001; 115: 1015–1022.

    Article  CAS  PubMed  Google Scholar 

  26. Schrezenmeier H, Hertenstein B, Wagner B, Raghavachar A, Heimpel H . A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. Exp Hematol 1995; 23: 81–87.

    CAS  PubMed  Google Scholar 

  27. Mukhina GL, Buckley JT, Barber JP, Jones RJ, Brodsky RA . Multilineage glycosylphosphatidylinositol anchor deficient hematopoiesis in untreated aplastic anemia. Br J Haematol 2001; 115: 476–482.

    Article  CAS  PubMed  Google Scholar 

  28. Nissen C, Genitsch A, Sendelov S, Dalle CV, Wodnar-Filipowicz A . Cell cycling stress in the monocyte line as a risk factor for progression of the aplastic anaemia/paroxysmal nocturnal haemoglobinuria syndrome to myelodysplastic syndrome. Acta Haematol 2000; 103: 33–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    R A Brodsky & R J Jones

Authors
  1. R A Brodsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R J Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R A Brodsky.

Additional information

Grant support: RAB is a Clinical Scholar of the Leukemia and Lymphoma Society of America.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brodsky, R., Jones, R. Riddle: What do aplastic anemia, acute promyelocytic leukemia, and chronic myeloid leukemia have in common?. Leukemia 18, 1740–1742 (2004). https://doi.org/10.1038/sj.leu.2403487

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403487

Keywords

This article is cited by

Search

Advanced search

Quick links