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Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy

Leukemia volume 15, pages 1848–1851 (2001)Cite this article

Abstract

Eighty-two unselected cases of therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) were investigated for internal tandem duplications of the FLT3gene (FLT3/ITD), for internal tandem duplications of the MLL gene (MLL/ITD) and for mutations of the WT1 gene. FLT3/ITD were observed in three patients, another two patients presented MLL/ITD whereas mutations of the WT1 gene were not observed. All FLT3/ITD included the tyrosine-rich stretch between codons 589 and 599, and both MLL/ITD presented break points within Alu-repeats, as previously observed in de novo AML. The ITD were not related to any specific type of previous therapy, but three out of the five cases were observed among only six patients with overt t-AML and a normal karyotype (P = 0.0043). Interestingly, one of the patients with FLT3/ITD presented overt t-AML of subtype M1 with a normal karyotype after treatment with an alkylating agent. Complete remission was observed following treatment with daunorubicin and cytosine arabinoside, but after 37 months the patient relapsed with t-AML of subtype M3 with a t(15;17) and the same FLT3/ITD was still present. Thus FLT3/ITD may in this case represent a primary event in leukemogenesis, whereas the t(15;17) may represent a secondary event most likely induced by subsequent therapy. In conclusion, FLT3/ITD and MLL/ITD are mainly observed in uncharacteristic cases of t-AML with a normal karyotype and unrelated to previous therapy for which reason they could represent sporadic cases of de novoAML.

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References

  1. Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P . Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia Blood 1995 86: 3542–3552

    CAS  PubMed  Google Scholar 

  2. Le Beau MM, Albain KS, Larson RA, Vardiman JW, Davis EM, Blough RR, Golomb HM, Rowley JD . Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes Nos. 5 and 7 J Clin Oncol 1986 4: 325–345

    Article  CAS  PubMed  Google Scholar 

  3. Johansson B, Mertens F, Heim S, Kristofferson U, Mitelman F . Cytogenetics of secondary myelodysplasia (sMDS) and acute nonlymphocytic leukemia (sANLL) Eur J Haematol 1991 47: 17–27

    Article  CAS  PubMed  Google Scholar 

  4. Horiike S, Misawa S, Kaneko H, Sasai Y, Kobayashi M, Fujii H, Tanaka S, Yagita M, Abe T, Kashima K, Taniwaki M . Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype Leukemia 1999 13: 1235–1242

    Article  CAS  PubMed  Google Scholar 

  5. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Mutations with loss of heterozygosity of p53 are common in therapy-related MDS and AML after exposure to alkylating agents, and significantly associated with deletion or loss of 5q, a complex karyotype and a poor prognosis J Clin Oncol 2001 19: 1405–1413

    Article  CAS  PubMed  Google Scholar 

  6. Andersen MK, Pedersen-Bjergaard J . Increased frequency of dicentric chromosomes in therapy-related MDS and AML compared to de novo disease is significantly related to previous treatment with alkylating agents and suggests a specific susceptibility to chromosome breakage at the centromere Leukemia 2000 14: 105–111

    Article  CAS  PubMed  Google Scholar 

  7. Michaux L, Wlodarska I, Stul M, Dierlamm J, Mugneret F, Herens C, Beverloo B, Verhest A, Verellen-Dumoulin C, Verhoef G, Selleslag D, Madoe V, Lecomte M, Deprijck B, Ferrant A, Delannoy A, Marichal S, Duhem C, Dicato M, Hagemeijer A . MLL amplification in myeloid leukemias: a study of 14 cases with multiple copies of 11q23 Genes Chromosomes Cancer 2000 29: 40–47

    Article  CAS  PubMed  Google Scholar 

  8. Andersen MK, Christiansen DH, Kirchhoff M, Pedersen-Bjergaard J . Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents Genes Chromosomes Cancer 2001 31: 33–41

    Article  CAS  PubMed  Google Scholar 

  9. Pedersen-Bjergaard J, Philip P . Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following cytostatic agents targeting at DNA-topoisomerase II Blood 1991 78: 1147–1148

    CAS  PubMed  Google Scholar 

  10. Larson RA, Le Beau MM, Ratain MJ, Rowley JD . Balanced translocations involving chromosome bands 11q23 and 21q22 in therapy-related leukemia Blood 1992 79: 1892–1893

    CAS  PubMed  Google Scholar 

  11. Pedersen-Bjergaard J, Rowley JD . The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation Blood 1994 83: 2780–2786

    CAS  PubMed  Google Scholar 

  12. Pedersen-Bjergaard J, Andersen MK, Johansson B . Balanced chromosome aberrations in leukemias following chemotherapy with DNA-topoisomerase II inhibitors J Clin Oncol 1998 16: 1897–1898

    Article  CAS  PubMed  Google Scholar 

  13. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S . Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia Leukemia 1996 10: 1911–1918

    CAS  PubMed  Google Scholar 

  14. Horiike S, Yokota S, Nakao M, Iwai T, Sasai Y, Kaneko H, Taniwaki M, Kashima K, Fujii H, Abe T, Misawa S . Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia Leukemia 1997 11: 1442–1446

    Article  CAS  PubMed  Google Scholar 

  15. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, Sonoda Y, Abe T, Kahsima K, Matsuo Y, Naoe T . Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines Leukemia 1997 11: 1605–1609

    Article  CAS  PubMed  Google Scholar 

  16. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R . Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia Blood 1999 93: 3074–3080

    CAS  PubMed  Google Scholar 

  17. Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK, Bernstein ID, Radich JP . Prevalence and prognostic significance of FLT3 internal tandem duplication in pediatric acute myeloid leukemia Blood 2001 97: 89–94

    Article  CAS  PubMed  Google Scholar 

  18. Schnittger S, Schoch C, Kern W, Staib P, Wuchter C, Sauerland MC, Serve H, Buechner T, Haferlach T, Hiddemann W . FLT3 length mutations in AML: correlation to cytogenetics, FAB-subtype, and prognosis in 652 patients Blood 2000 96: 826a (Abstr.)

    Google Scholar 

  19. Caligiuri MA, Strout MP, Schichman SA, Mrozek K, Arthur DC, Herzig GP, Baer MR, Schiffer CA, Heinonen K, Knuutila S, Nousiainen T, Ruutu T, Block AW, Schulman P, Pedersen-Bjergaard J, Croce CM, Bloomfield CD . Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11 Cancer Res 1996 56: 1418–1425

    CAS  PubMed  Google Scholar 

  20. Schichman SA, Caligiuri MA, Gu Y, Strout MP, Canaani E, Bloomfield CD, Croce CM . ALL-1 partial duplication in acute leukemia Proc Natl Acad Sci USA 1994 91: 6236–6239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Strout MP, Marcucci G, Bloomfield CD, Caligiuri MA . The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia Proc Natl Acad Sci USA 1998 95: 2390–2395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T, Buchner T, Wormann B, Hiddemann W, Griesinger F . Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML Leukemia 2000 14: 796–804

    Article  CAS  PubMed  Google Scholar 

  23. Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F, Knuutila S, Mrozek K, Oberkircher AR, Marcucci G, de la Chapelle A, Elonen E, Block AW, Rao PN, Herzig GP, Powell BL, Ruutu T, Schiffer CA, Bloomfield CD . Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics Cancer Res 1998 58: 55–59

    CAS  PubMed  Google Scholar 

  24. King-Underwood L, Renshaw J, Pritchard-Jones K . Mutations in the Wilms’ tumor gene WT1 in leukemias Blood 1996 87: 2171–2179

    CAS  PubMed  Google Scholar 

  25. Algar E, Blackburn D, Kromykh T, Taylor G, Smith P . Mutation analysis of the WT1 gene in sporadic childhood leukaemia Leukemia 1997 11: 110–113

    Article  CAS  PubMed  Google Scholar 

  26. Carapeti M, Goldman JM, Cross NC . Dominant-negative mutations of the Wilms’ tumour predisposing gene (WT1) are infrequent in CML blast crisis and de novo acute leukaemia Eur J Haematol 1997 58: 346–349

    Article  CAS  PubMed  Google Scholar 

  27. Miyagawa K, Hayashi Y, Fukuda T, Mitani K, Hirai H, Kamiya K . Mutations of the WT1 gene in childhood nonlymphoid hematological malignancies Genes Chromosomes Cancer 1999 25: 176–183

    Article  CAS  PubMed  Google Scholar 

  28. King-Underwood L, Pritchard-Jones K . Wilms’ tumor (WTI) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance Blood 1998 91: 2961–2968

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Danish Cancer Society, HS forskningspulje 1997 and Anders Hasselbalchs Foundation. The authors are indebted to Ms Helle Thrane for technical assistance in the molecular studies. Furthermore, we want to thank Dr Steven A Schichman for providing the B859 probe and Mr Harry Cowan BSc and Professor Flemming Skovby MD, PhD for their help in preparing the manuscript.

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  1. Department of Clinical Genetics, Section of Hematology and Oncology, Cytogenetic Laboratory, Juliane Marie Centre, Section 4052, Rigshospitalet, Blegdamsvej 9, Copenhagen Ø, 2100, Denmark

    DH Christiansen & J Pedersen-Bjergaard

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Christiansen, D., Pedersen-Bjergaard, J. Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy. Leukemia 15, 1848–1851 (2001). https://doi.org/10.1038/sj.leu.2402246

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