The use of gene expression profiling to identify novel minimal residual disease markers (MRD) in acute myeloid leukaemia (AML)

Doctoral thesis English OPEN
Woodward, Eleanor
  • Subject: R1
    mesheuropmc: hemic and lymphatic diseases

Acute myeloid leukaemia (AML) is a heterogeneous disorder characterised by the accumulation of immature haematopoietic cells blocked at various stages of differentiation. Despite improved survival rates over the past decade, relapse occurs in approximately 70% patients undergoing chemotherapy. A potential reason for this is that current clinical protocols do not take account of the level of residual disease present at remission. Therefore, one strategy to reduce relapse rates is to monitor minimal residual disease and continue to treat until the patient is minimal residual disease negative. Current minimal residual disease markers are available for patients with characterised fusion genes but approximately 50% of patients have no detectable chromosomal aberration and therefore are without markers. Gene expression profiling is a powerful tool for disease classification, prognosis and therapeutic predictions. This study aimed to investigate the use gene expression profiling to identify novel minimal residual disease markers for specific AML sub-groups. Patient diagnostic samples were profiled to identify genes specific to AML patients with a favourable translocation in order to establish the "proof-of-principle". Several genes identified were followed in patient diagnostic and follow- up samples and compared to the markers currently used. Continuing with normal karyotype AML, genes were identified as specific to this sub-group. Several homeobox (HOX) genes and the Wilms' tumour (WT1) gene were identified and their MRD levels followed in diagnostic and follow-up samples. Only WT1 identified as specific to normal karyotype AML met the necessary criteria to be an MRD marker. Although the majority of genes selected from the GEP in this study proved unsuitable as markers, the identification and validation of a marker already used for MRD monitoring, WT1, demonstrates the ability of gene expression profiling to identify potential minimal residual disease markers in normal karyotype AML.
  • References (145)
    145 references, page 1 of 15

    Martin,F.H., Suggs,S.V., Langley,K.E., Lu,H.S., Ting.J., Okino.K.H., Morris,C.F., McNiece.I.K., Jacobsen,F.W., Mendiaz.E.A., & . (1990) Primary structure and functional expression of rat and human stem cell factor DNAs. Cell, 63, 203-211.

    Martin-Villar,E., Megias.D., Castel,S., Yurrita.M.M., Vilaro.S., & Quintanilla,M. (2006) Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J.Cell Scl., 119, 4541-4553.

    Martin-Villar,E., Scholl,F.G., Gamallo,C., Yurrita.M.M., MunozGuerra.M., Cruces,J., & Quintanilla,M. (2005) Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int.J. Cancer, 113, 899-910.

    Martineau.M., Berger,R., Lillington.D.M., Moorman,A.V., & SeckerWalker.L.M. (1998) The t(6;11)(q27;q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases. EU Concerted Action 11q23 Workshop participants. Leukemia, 12, 788-791.

    Mason,K.D., Juneja.S.K., & Szer.J. (2006) The immunophenotype of acute myeloid leukemia: is there a relationship with prognosis? Blood Rev., 20, 71-82.

    Matsushita, M., Ikeda.H., Kizaki.M., Okamoto.S., Ogasawara.M., Ikeda.Y., & Kawakami.Y. (2001) Quantitative monitoring of the PRAME gene for the detection of minimal residual disease in leukaemia. Br.J.Haematol., 112, 916-926.

    McCulloch.E.A. (1983) Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture, 1982). Blood, 62, 1-13.

    Mead.A.J., Gale.R.E., Hills,R.K., Gupta,M., Young,B.D., Burnett,A.K., & Linch.D.C. (2008) Conflicting data on the prognostic significance of FLT3/TKD mutations in acute myeloid leukemia might be related to the incidence of biallelic disease. Blood, 112, 444-445.

    Mehrotra.B., George,T.I., Kavanau.K., vet-Loiseau,H., Moore,D., Willman.C.L., Slovak,M.L., Atwater,S., Head.D.R., & Pallavicini.M.G. (1995) Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia. Blood, 86, 1139-1147.

    Meshinchi.S. & Appelbaum.F.R. (2009) Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin.Cancer Res., 15, 4263-4269.

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