Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase

Nagy, Etelka; Beck, Zoltán; Kiss, Attila; Csoma, Eszter; Telek, B; Kónya, József; Oláh, Éva; Rák, K.; Tóth, Ferenc

doi:10.1016/s0959-8049(03)00552-5

Cited by 39 publications

(21 citation statements)

References 23 publications

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“…In haematological cancers, apart from the accelerated phase of chronic myeloid leukaemia, where 40% of patients carried p14 hypermethylation,33 infrequent p14 hypermethylation has been reported in 3–8% of ALL,29 32 but not in t-MDS/AML (n = 81) 34. Our finding of absent p14 hypermethylation in acute leukaemia suggested that p14 is not targeted by methylation in the dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 pathway.…”

Section: Discussionmentioning

confidence: 57%

Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias

2008

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Section: Discussionmentioning

confidence: 57%

Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias

2008

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“…46) However, incursion of DNA damage, or activation of p53 by ARF under oncogenic stimulation, as is the case in CML cells, may be sufficient to tip the balance towards apoptosis, even in the presence of STI571. This may reflect the situation in the chronic phase of CML, where p53 and ARF mutations are rarely mutated [5][6][7]47,48 and cells respond well to STI571 treatment. 4 This would not be the case in CML cells lacking functional p53, as in the blast crisis phase.…”

Section: Discussionmentioning

confidence: 93%

Treatment of Chronic Myeloid Leukemia Cells with Imatinib (STI571) Impairs p53 Accumulation in Response to DNA Damage

Goldberg¹,

Levav²,

Krichevsky³

et al. 2004

Cell Cycle

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Chronic myelogenous leukaemia (CML) is induced by the Bcr-Abl fusion protein.Inhibition of Bcr-Abl by STI571 is widely used to treat CML patients. Unlike in most cancer types, the frequency of p53 mutations in CML is low. Here, we investigated the effect of STI571 treatment of CML cells on p53 regulation. Exposure of CML cells, including established cell lines and freshly isolated cells from patients, to STI571 reduced p53 protein levels, and severely impaired its accumulation in response to DNA damage. This may be explained by the status of p53 serine 20 phosphorylation. In non-stressed CML cells, serine 20 of p53 is constitutively phosphorylated by Chk1, and is inhibited by STI571. In response to DNA damage, however, this phosphorylation is mediated by Chk1 and Chk2, and is only partially inhibited by STI571. CML cells expressing wild-type p53 are more resistant to treatment with STI571, but moderately more sensitive to DNA damage, than CML cells lacking p53. An enhanced induction of apoptosis by STI571 and DNA damage is observed in CML cells bearing wild-type p53, but not in cells lacking functional p53. This implies that the status of p53 may affect the response of CML cells to this combined treatment.

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“…In such cell context, Cby1 lower expression compared with more differentiated myeloid progenitors arises from transcriptional events driven by DNA hypermethylation at the gene promoter (Figures 4 and 5, Table S4 and Figure S4). Notably, the hypermethylation at DNA promoter-associated CpG islands is a common mechanism of tumor suppressor gene silence in CML at some instances associated with the disease progression and/or IM resistance [30], [32], [39], [45]. It is worth noting that Cby1 transcriptional downmodulation proceeding from promoter hypermethylation was also apparent in CD34+ cell from HP, supporting the central role of Cby1 in beta catenin signaling of HSC (Figure 4 and 5, Table S4 and Figure S3) [44].…”

Section: Discussionmentioning

confidence: 99%

BCR-ABL1-Associated Reduction of Beta Catenin Antagonist Chibby1 in Chronic Myeloid Leukemia

et al. 2013

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Beta Catenin signaling is critical for the self-renewal of leukemic stem cells in chronic myeloid leukemia. It is driven by multiple events, enhancing beta catenin stability and promoting its transcriptional co-activating function. We investigated the impact of BCR-ABL1 on Chibby1, a beta catenin antagonist involved in cell differentiation and transformation. Relative proximity of the Chibby1 encoding gene (C22orf2) on chromosome 22q12 to the BCR breakpoint (22q11) lets assume its involvement in beta catenin activation in chronic myeloid leukemia as a consequence of deletions of distal BCR sequences encompassing one C22orf2 allele. Forty patients with chronic myeloid leukemia in chronic phase were analyzed for C22orf2 relocation and Chibby1 expression. Fluorescent in situ hybridization analyses established that the entire C22orf2 follows BCR regardless of chromosomes involved in the translocation. In differentiated hematopoietic progenitors (bone marrow mononuclear cell fractions) of 30/40 patients, the expression of Chibby1 protein was reduced below 50% of the reference value (peripheral blood mononuclear cell fractions of healthy persons). In such cell context, Chibby1 protein reduction is not dependent on C22orf2 transcriptional downmodulation; however, it is strictly dependent upon BCR-ABL1 expression because it was not observed at the moment of major molecular response under tyrosine kinase inhibitor therapy. Moreover, it was not correlated with the disease prognosis or response to therapy. Most importantly, a remarkable Chibby1 reduction was apparent in a putative BCR-ABL1+ leukemic stem cell compartment identified by a CD34+ phenotype compared to more differentiated hematopoietic progenitors. In CD34+ cells, Chibby1 reduction arises from transcriptional events and is driven by C22orf2 promoter hypermethylation. These results advance low Chibby1 expression associated with BCR-ABL1 as a component of beta catenin signaling in leukemic stem cells.

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Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase

Cited by 39 publications

References 23 publications

Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias

Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias

Treatment of Chronic Myeloid Leukemia Cells with Imatinib (STI571) Impairs p53 Accumulation in Response to DNA Damage

BCR-ABL1-Associated Reduction of Beta Catenin Antagonist Chibby1 in Chronic Myeloid Leukemia

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