Molecular biology of therapy-related leukaemias

Joannides, Melanie; Grimwade, David

doi:10.1007/s12094-010-0460-5

Cited by 38 publications

(48 citation statements)

References 55 publications

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“…[7][8][9][10][11] The MLL gene is rearranged most often in de novo infant leukemia and in adult secondary therapy-related leukemia. [12][13][14] MLL-r functions as the initiating, and perhaps as the sole driving, oncogenic event by dysregulating epigenetic/transcriptional programs. 15,16 The most common rearrangement is a reciprocal translocation between MLL and a partner gene resulting in a chimeric protein composed of the N terminus domain of MLL and C terminus domain of the partner gene.…”

Section: Introductionmentioning

confidence: 99%

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Sanjuán-Pla

Bueno

Prieto

et al. 2015

Blood

101

138

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Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a “multiple-and-sequential-hit” model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one “big-hit” might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models.

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Section: Introductionmentioning

confidence: 99%

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Sanjuán-Pla

Bueno

Prieto

et al. 2015

Blood

101

138

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“…This phenomenon has been studied extensively. The results obtained suggest that secondary leukaemias are associated with chromosomal translocations, which generate chimerical genes (for a review, see [19-21]). The spectrum of genes affected by translocations in secondary leukaemias is clearly non-random, which could be explained both by a certain specificity of initial translocation events and by the subsequent selection of cellular clones that have an advantage in survival and proliferation [22].…”

Section: Introductionmentioning

confidence: 99%

The Broken MLL Gene Is Frequently Located Outside the Inherent Chromosome Territory in Human Lymphoid Cells Treated with DNA Topoisomerase II Poison Etoposide

et al. 2013

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The mixed lineage leukaemia (MLL) gene is frequently rearranged in secondary leukaemias, in which it could fuse to a variety of different partners. Breakage in the MLL gene preferentially occurs within a ~8 kb region that possesses a strong DNA topoisomerase II cleavage site. It has been proposed that DNA topoisomerase II-mediated DNA cleavage within this and other regions triggers translocations that occur due to incorrect joining of broken DNA ends. To further clarify a possible mechanism for MLL rearrangements, we analysed the frequency of MLL cleavage in cells exposed to etoposide, a DNA topoisomerase II poison commonly used as an anticancer drug, and positioning of the broken 3’-end of the MLL gene in respect to inherent chromosomal territories. It was demonstrated that exposure of human Jurkat cells to etoposide resulted in frequent cleavage of MLL genes. Using MLL-specific break-apart probes we visualised cleaved MLL genes in ~17% of nuclei. Using confocal microscopy and 3D modelling, we demonstrated that in cells treated with etoposide and cultivated for 1 h under normal conditions, ~9% of the broken MLL alleles were present outside the chromosome 11 territory, whereas in both control cells and cells inspected immediately after etoposide treatment, virtually all MLL alleles were present within the chromosomal territory. The data are discussed in the framework of the “breakage first” model of juxtaposing translocation partners. We propose that in the course of repairing DNA topoisomerase II-mediated DNA lesions (removal of stalled DNA topoisomerase II complexes and non-homologous end joining), DNA ends acquire additional mobility, which allows the meeting and incorrect joining of translocation partners.

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“…12−14,17−24 Initially, as many as 12% of patients treated with etoposide developed t-AMLs. 19−22,25 Once high-risk schedules were identified and eliminated, that number subsequently dropped to ∼2–3%.…”

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confidence: 99%

Etoposide Quinone Is a Covalent Poison of Human Topoisomerase IIβ

Smith

Byl²,

Mercer

et al. 2014

Biochemistry

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Etoposide is a topoisomerase II poison that is utilized to treat a broad spectrum of human cancers. Despite its wide clinical use, 2–3% of patients treated with etoposide eventually develop treatment-related acute myeloid leukemias (t-AMLs) characterized by rearrangements of the MLL gene. The molecular basis underlying the development of these t-AMLs is not well understood; however, previous studies have implicated etoposide metabolites (i.e., etoposide quinone) and topoisomerase IIβ in the leukemogenic process. Although interactions between etoposide quinone and topoisomerase IIα have been characterized, the effects of the drug metabolite on the activity of human topoisomerase IIβ have not been reported. Thus, we examined the ability of etoposide quinone to poison human topoisomerase IIβ. The quinone induced ∼4 times more enzyme-mediated DNA cleavage than did the parent drug. Furthermore, the potency of etoposide quinone was ∼2 times greater against topoisomerase IIβ than it was against topoisomerase IIα, and the drug reacted ∼2–4 times faster with the β isoform. Etoposide quinone induced a higher ratio of double- to single-stranded breaks than etoposide, and its activity was less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIβ when it was incubated with the enzyme prior to the addition of DNA. These results are consistent with the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis through an interaction with topoisomerase IIβ.

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Molecular biology of therapy-related leukaemias

Cited by 38 publications

References 55 publications

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

The Broken MLL Gene Is Frequently Located Outside the Inherent Chromosome Territory in Human Lymphoid Cells Treated with DNA Topoisomerase II Poison Etoposide

Etoposide Quinone Is a Covalent Poison of Human Topoisomerase IIβ

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