Allele-specific replication associated with aneuploidy in blood cells of patients with hematologic malignancies

Korenstein-Ilan, Avital; Amiel, Aliza; Lalezari, Shadan; Lishner, Michael; Avivi, Lydia

doi:10.1016/s0165-4608(02)00610-6

Cited by 34 publications

(42 citation statements)

References 35 publications

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“…It is also consistent with our findings that an increase in chr3 copy number resulted in asynchronous replication and incomplete replication within the late-replicating regions. Asynchronous replication was proposed as a prominent tumor cell characteristic (Korenstein-Ilan et al, 2002). Defects in replication timing were found to be associated with defects in chromosome condensation, sister chromatid cohesion, and genome stability (Loupart et al, 2000;Pflumm and Botchan, 2001;Smith et al, 2001).…”

Section: Asynchronous Replication Of Supranumerary Chromosomal Loci Amentioning

confidence: 99%

Microcell‐mediated chromosome transfer provides evidence that polysomy promotes structural instability in tumor cell chromosomes through asynchronous replication and breakage within late‐replicating regions

Kost‐Alimova

Fedorova

Yang

et al. 2004

Genes Chromosomes & Cancer

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It was reported earlier that normal chromosome 3 (chr3) transfer into tumor cells of different origin may suppress their ability to grow in SCID mice. Tumorigenicity may be restored by the loss of certain 3p regions. We transferred a normal cell-derived chr3 into cells of a human renal cell carcinoma line and followed the chromosomal changes during in vivo and in vitro growth. In cells cultivated for 6 weeks or more and in the tumors grown in SCID mice, supernumerary chrs3 were always rearranged, accompanied by 3p losses. Unexpectedly, we found that the rearrangements affected not only the transferred exogenous chr3, but also the endogenous chrs3. Other chromosomes that were polysomic in the recipient cells were affected as well, suggesting that polysomy may be associated with structural chromosome instability. The dominant chromosomal aberrations were unbalanced translocations with preferentially pericentromeric breakpoints. The breakpoint distribution on chr3 preferentially affected the pericentromeric 3p11 (8 breaks) and 3p12-13 (5 breaks) regions. The regions 3p14 and 3q26-27 occasionally were involved as well (one break in each case). These four regions were the latest replicating, as shown by BrdU incorporation-based replication banding. Using fluorescence in situ hybridization-based replication timing, we detected asynchronous and incomplete centromere replication in cells with 3 or 4 copies of chr3, but not in cells with 2. We concluded that in tumor cells, asynchronous and incomplete replication of polysomic chromosomal parts is associated with aberrations that have breakpoints within the late-replicating regions. This may explain the increased structural chromosome instability and preferential pericentromeric localization of breakpoints in hyperploid tumors.

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Section: Asynchronous Replication Of Supranumerary Chromosomal Loci Amentioning

confidence: 99%

Microcell‐mediated chromosome transfer provides evidence that polysomy promotes structural instability in tumor cell chromosomes through asynchronous replication and breakage within late‐replicating regions

Kost‐Alimova

Fedorova

Yang

et al. 2004

Genes Chromosomes & Cancer

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“…Applying the FISH replication assay to biallelically expressed genes in cells of cancer patients indicated that malignancy is associated with non-disease-specific loss of the normally synchronous pattern of replication of certain loci. Briefly, biallelically expressed genes, -- such as TP53 , AML1 , RB1, C-MYC and HER2 (which normally display a synchronous mode of replication) -- exhibit an asynchronous pattern of replication (similar to that of monoallelically expressed genes) in bone marrow cells [15] and blood lymphocytes [16] of patients with hematological malignancies, and even in blood lymphocytes of patients with solid tumors, such as renal cell carcinoma [7] or prostate cancer [8,17]. …”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, chromosome-specific sequences (pericentromeric, unexpressed DNA arrays), which normally display synchrony in replication of homologous counterparts, similar to biallelically expressed genes, change their inherent replication mode and replicate asynchronously in lymphocytes of patients with cancer, including ovarian [18], hematological [16] and prostate [8,17] malignancies. This change in the replication patterns of the pericentromeric arrays is accompanied by chromosomal malsegregation, which results in increased aneuploidy in the patients' cells [8,16,18].…”

Section: Introductionmentioning

confidence: 99%

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The aberrant asynchronous replication — characterizing lymphocytes of cancer patients — is erased following stem cell transplantation

et al. 2010

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BackgroundAberrations of allelic replication timing are epigenetic markers observed in peripheral blood cells of cancer patients. The aberrant markers are non-cancer-type-specific and are accompanied by increased levels of sporadic aneuploidy. The study aimed at following the epigenetic markers and aneuploidy levels in cells of patients with haematological malignancies from diagnosis to full remission, as achieved by allogeneic stem cell transplantation (alloSCT).MethodsTP53 (a tumor suppressor gene assigned to chromosome 17), AML1 (a gene assigned to chromosome 21 and involved in the leukaemia-abundant 8;21 translocation) and the pericentomeric satellite sequence of chromosome 17 (CEN17) were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosomes 17 and 21. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization (FISH) technology applied to phytohemagglutinin (PHA)-stimulated lymphocytes.ResultsWe show that aberrant epigenetic markers are detected in patients with hematological malignancies from the time of diagnosis through to when they are scheduled to undergo alloSCT. These aberrations are unaffected by the clinical status of the disease and are displayed both during accelerated stages as well as in remission. Yet, these markers are eradicated completely following stem cell transplantation. In contrast, the increased levels of aneuploidy (irreversible genetic alterations) displayed in blood lymphocytes at various stages of disease are not eliminated following transplantation. However, they do not elevate and remain unchanged (stable state). A demethylating anti-cancer drug, 5-azacytidine, applied in vitro to lymphocytes of patients prior to transplantation mimics the effect of transplantation: the epigenetic aberrations disappear while aneuploidy stays unchanged.ConclusionsThe reversible nature of the replication aberrations may serve as potential epigenetic blood markers for evaluating the success of transplant or other treatments and for long-term follow up of the patients who have overcome a hematological malignancy.

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“…It was previously demonstrated by Dotan et al [2004Dotan et al [ , 2008 that by introducing 5-azacytidine, a DNA-methyltransferase inhibitor, the asynchronous replication of lymphocytes from patients with prostate cancer, as well as various hematological malignancies [Korenstein-Ilan et al, 2002], could be reversed into a synchronized pattern, indicating that DNA hypermethylation is implicated in the mechanism of allelic replication alterations. It is reasonable to assume that the mechanism giving rise to this aberration might occur in various other malignancies or premalignant conditions such as PSC.…”

Section: Discussionmentioning

confidence: 99%

Asynchronous Replication in Lymphocytes from Patients with Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Laish

Biron‐Shental²,

Katz³

et al. 2015

Cytogenet Genome Res

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Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are associated chronic inflammatory diseases with malignant potential. Loss of replication synchrony during the S-phase of the cell cycle has been shown to be linked to several malignant and premalignant states. This study evaluated temporal differences in replication timing between these diseases. The replication pattern of peripheral blood lymphocytes obtained from patients with PSC and IBD and healthy individuals was analyzed by fluorescence in situ hybridization (FISH) in 2 pairs of alleles, in 15qter and 13qter. Asynchrony was determined by the presence of 1 single and 1 set of double dots in the same cell. Samples from subjects with PSC showed significantly greater temporal differences in replication timing, in contrast to the high level of synchrony observed in samples from healthy individuals (p = 0.045). Samples from IBD patients exhibited a nonsignificant increase in replication asynchrony. We believe that these results reflect impairment in the replication control of structural homologous loci in PSC, and that this phenomenon may be correlated with the inflammation-induced malignant potential of this condition.

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Allele-specific replication associated with aneuploidy in blood cells of patients with hematologic malignancies

Cited by 34 publications

References 35 publications

Microcell‐mediated chromosome transfer provides evidence that polysomy promotes structural instability in tumor cell chromosomes through asynchronous replication and breakage within late‐replicating regions

Microcell‐mediated chromosome transfer provides evidence that polysomy promotes structural instability in tumor cell chromosomes through asynchronous replication and breakage within late‐replicating regions

The aberrant asynchronous replication — characterizing lymphocytes of cancer patients — is erased following stem cell transplantation

Asynchronous Replication in Lymphocytes from Patients with Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

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