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. 2014 Oct-Dec;207(10-12):467-73.
doi: 10.1016/j.cancergen.2014.09.001. Epub 2014 Sep 16.

High frequency of rare structural chromosome abnormalities at relapse of cytogenetically normal acute myeloid leukemia with FLT3 internal tandem duplication

Theodore S Gourdin  1 , Ying Zou  2 , Yi Ning  2 , Ashkan Emadi  1 , Vu H Duong  1 , Michael L Tidwell  1 , Ching Chen  2 , Feyruz V Rassool  3 , Maria R Baer  4
Affiliations

High frequency of rare structural chromosome abnormalities at relapse of cytogenetically normal acute myeloid leukemia with FLT3 internal tandem duplication

Theodore S Gourdin et al. Cancer Genet. 2014 Oct-Dec.

Abstract

FLT3 internal tandem duplication (ITD) mutations are present in acute myeloid leukemia (AML) in 30% of patients with acute myeloid leukemia (AML), most commonly in those with a normal karyotype, and are associated with short relapse-free survival. Both in vitro and in vivo studies of FLT3-ITD cell lines have demonstrated reactive oxygen species-mediated DNA double-strand breaks and associated error-prone DNA repair as a mechanism of genomic instability, and we hypothesized that genomic instability might be manifested by cytogenetic changes at relapse of FLT3-ITD AML. We retrospectively reviewed charts of patients with cytogenetically normal (CN) FLT3-ITD AML treated at the University of Maryland Greenebaum Cancer Center, with attention to metaphase analysis results at relapse. Cytogenetic data were available from first and, when applicable, subsequent relapses for 15 patients diagnosed with CN FLT3-ITD AML. Among 12 patients with documented FLT3-ITD at first and, when applicable, subsequent relapse, 10 had cytogenetic changes, including nine with rare structural abnormalities. The high frequency of rare structural chromosome abnormalities at relapse in our case series supports a role of genomic instability in the genesis of relapse, and suggests that reactive oxygen species-generating and DNA repair pathways might be therapeutic targets in FLT3-ITD AML.

Keywords: Acute myeloid leukemia; FLT3-ITD; cytogenetics; genomic instability; relapse.

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Conflict of interest statement

Conflict of Interest: None of the authors of this manuscript have any undisclosed conflicts of interest to report.

Figures

Figure 1.
Figure 1.. Representative relapse metaphase karyotypes.
Representative metaphase karyotypes from three of the FLT3-ITD patients in Table1, Patients 3, 4, and 7, labeled A, B and C, respectively. Panel D, contains enlarged views of the structural abnormalities in each of these patients.
Figure 2.
Figure 2.. Chromosome and SNP microarray results of Patient 9.
A. G-band karyogram in the relapse sample. Arrows point to abnormal chromosomes including monosomy 17 and 22, rearrangements of 2q21, 3q12, 6p22 and 7p15, possible deletion of 11p, and gain of two marker chromosomes. B. SNP microarray profiles from the diagnosis and relapse samples.
See this image and copyright information in PMC

References

    1. Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87:1089–96. - PubMed
    1. Rosnet O, Bühring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996;10:238–48. - PubMed
    1. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–9. - PubMed
    1. Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372–80. - PubMed
    1. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood. 2002;100:59–66. - PubMed

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