Therapy‐related acute lymphoblastic leukaemia with <i>MLL</i> rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992

Andersen, Mette Klarskov; Christiansen, Debes H.; Jensen, Bente; Ernst, Peter; Hauge, Gunnar; Pedersen‐Bjergaard, Jens

doi:10.1046/j.1365-2141.2001.03000.x

Cited by 126 publications

(83 citation statements)

References 21 publications

(19 reference statements)

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“…38,39 Within the AML1 locus at 21q22, a reproducible induction of a highly specific double-strand DNA cleavage by topoisomerase inhibitors was described as well. 40,41 In contrast to these findings in MLL and AML1 rearrangements, the mechanism of breakage in CBFB-MYH11 is unclear. V(D)J recombination was suggested at least for the type A variants.…”

Section: Tablementioning

confidence: 45%

Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients

et al. 2007

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Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients The spectrum of CBFB-MYH11 fusion transcripts in acute myeloid leukemia (AML) M4eo with inv(16)/t(16;16) is heterogeneous. Approximately 85% show type A CBFB-MYH11 fusion transcripts. In addition, more than 10 different fusion transcripts have been reported. The prognostic impact and biological background of rare fusion transcripts remain open. In this study, a molecular characterization of CBFB-MYH11 transcripts in 162 patients with CBFB-MYH11 positive AML at diagnosis was performed. In total, 128 patients (79.0%) showed the fusion transcript type A, whereas nine different rare CBFB-MYH11 fusion genes were detected in 34 cases (21.0%). Rare fusion transcripts were found more frequently in therapy-related AML (P ¼ 0.0106). Numerical gains of the chromosomes 8, 21 and 22 were more frequently associated with type A (28.3%) than with rare fusions (12.9%) (P ¼ 0.012). Median white blood cell (WBC) count was higher in type A (35.4 G/l; range ¼ 1.1-279 G/l) than in cases with rare types (7.8 G/l; range ¼ 0.8-148.0 G/l) (Po0.0001). Rare fusion transcripts were correlated with an atypical cytomorphology not primarily suggestive for the FAB subtype M4eo (P ¼ 0.0203). Immunophenotype revealed lower CD2, CD13, CD33 and CD90 levels than in type A fusion cases (P ¼ 0.036, 0.002, 0.029 and 0.045, respectively). However, the type of fusion was not an independent prognostic parameter.

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Section: Tablementioning

confidence: 45%

Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients

et al. 2007

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“…Despite the importance of topoisomerase II as a target for cancer chemotherapy, considerable evidence suggests that the enzyme also initiates chromosomal translocations that lead to specific types of leukemia [84,86,94,[139][140][141]. For example, ~2-3% of patients treated with regimens that include etoposide ultimately develop acute myelocytic leukemia [84,86,94,139,140].…”

Section: Non-covalent Topoisomerase II Poisonsmentioning

confidence: 99%

“…For example, ~2-3% of patients treated with regimens that include etoposide ultimately develop acute myelocytic leukemia [84,86,94,139,140]. Recently, correlations between the rising use of mitoxantrone to treat breast cancer and the development of secondary leukemias have been reported [142].…”

Section: Non-covalent Topoisomerase II Poisonsmentioning

confidence: 99%

“…Recently, correlations between the rising use of mitoxantrone to treat breast cancer and the development of secondary leukemias have been reported [142]. Over 50% of these leukemias display translocations within an 8.3 kb breakpoint cluster region in the MLL gene at chromosomal band 11q23 [84,86,94,139,140,143]. DNA breakpoints found in these secondary leukemias are in close proximity to topoisomerase II cleavage sites [144][145][146].…”

Section: Non-covalent Topoisomerase II Poisonsmentioning

confidence: 99%

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DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

361

466

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Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under-and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destablize the genome. This article discusses both aspects of human type II topoisomerases.

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“…67 MLL gene aberrations are also frequently found in patients with de novo AML and secondary AML following therapy including topoisomerase II inhibitors. 68,69 More than 54 different partner chromosome regions have now been identified, of which at least 37 partner genes are known (Table 4). 4,70 The t(4;11)(q21;q23) and t(11;19)(q23;p13.3) are the most common translocations in ALL, whereas t(6;11)(q27;q23), t(9;11)(p21-p22;q23), t(10;11)(p12;q23), and t(11;19)(q23;p13.1) are most frequent in AML.…”

Section: Translocations Involving the Mll Gene (11q23)mentioning

confidence: 99%

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

Burg

Poulsen²,

Hunger

et al. 2004

Leukemia

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Chromosome aberrations are frequently observed in precursor-B-acute lymphoblastic leukemias (ALL) and T-cell acute lymphoblastic leukemias (T-ALL). These translocations can form leukemia-specific chimeric fusion proteins or they can deregulate expression of an (onco)gene, resulting in aberrant expression or overexpression. Detection of chromosome aberrations is an important tool for risk classification. We developed rapid and sensitive split-signal fluorescent in situ hybridization (FISH) assays for six of the most frequent chromosome aberrations in precursor-B-ALL and T-ALL. The split-signal FISH approach uses two differentially labeled probes, located in one gene at opposite sites of the breakpoint region. Probe sets were developed for the genes TCF3 (E2A) at 19p13, MLL at 11q23, ETV6 at 12p13, BCR at 22q11, SIL-TAL1 at 1q32 and TLX3 (HOX11L2) at 5q35. In normal karyotypes, two colocalized green/red signals are visible, but a translocation results in a split of one of the colocalized signals. Split-signal FISH has three main advantages over the classical fusionsignal FISH approach, which uses two labeled probes located in two genes. First, the detection of a chromosome aberration is independent of the involved partner gene. Second, split-signal FISH allows the identification of the partner gene or chromosome region if metaphase spreads are present, and finally it reduces false-positivity. Leukemia ( Chromosome aberrations play an important role in hematological malignancies. 1 In ALL, most of these aberrations concern balanced translocations involving genes that play key roles in the development and function of lymphoid cells, such as transcription factors, cell cycle regulators, and signal transduction molecules. Balanced translocations can result in fusion of two genes that encode leukemia-specific chimeric (fusion) proteins. The fusion proteins have functional features that differ from the corresponding wild-type proteins and mostly play a role in leukemogenesis. In addition to the new features of the fusion protein, loss of wild-type activity due to the translocation (in some translocations enhanced by deletion of the second allele) might contribute to oncogenesis. Alternatively, chromosome translocations can result in deregulated expression of (onco)genes as a direct consequence of a translocation to a regulatory element, for example, an immunoglobulin (Ig) or T-cell receptor (TCR) enhancer. 2,3 The most frequent translocations in precursor-B-ALL are t(1;19)(q23;p13) t(4;11)(q21;q23), t(12;21)(p13;q22), and t(9;22)(q34;q11), all four of which result in generation of fusion genes. The t(1;19)(q23;p13) fuses the transcription factorencoding gene TCF3 (E2A) with the transcription factor PBX1. In t(4;11)(q21;q23), the MLL gene at 11q23, which encodes a putative DNA-binding protein, is translocated to the MLLT2 (AF4) gene. The MLL gene is involved in many other translocations in ALL and acute myeloid leukemia (AML). Until now, more than 30 partner genes have been identified. 4 The t(12;21)(p13;q22) involves th...

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Therapy‐related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992

Cited by 126 publications

References 21 publications

Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients

Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients

DNA topoisomerase II, genotoxicity, and cancer

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

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