Decreased TET2 gene expression during chronic myeloid leukemia progression

In chronic lymphocytic leukemia (CLL), NOTCH1 gene mutations (NOTCH1mut) have been associated with adverse prognostic features but the independence of these as a prognostic factor is still controversial. In our study we validated a c.7541-7542delCT NOTCH1 mutation assay based on droplet digital PCR (ddPCR); we also analyzed the NOTCH1mut allelic burden, expressed as fractional abundance (FA), in 88 CLL patients at diagnosis to assess its prognostic role and made a longitudinal ddPCR analysis in 10 cases harboring NOTCH1mut to verify the FA variation over time. Our data revealed that with the ddPCR approach the incidence of NOTCH1mut in CLL was much higher (53.4%) than expected. However, longitudinal ddPCR analysis of CLL cases showed a statistically significant reduction of the NOTCH1mut FA detected at diagnosis after treatment (median FA 11.67 % vs 0.09 %, respectively, p = 0.01); the same difference, in terms of NOTCH1mut FA, was observed in the relapsed cases compared to the NOTCH1mut allelic fraction observed in patients in complete or partial remission (median FA 4.75% vs 0.43%, respectively, p = 0.007). Our study demonstrated a much higher incidence of NOTCH1mut in CLL than has previously been reported, and showed that the NOTCH1mut allelic burden evaluation by ddPCR might identify patients in need of a closer clinical follow-up during the “watch and wait” interval and after standard chemotherapy.

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“…Chromosome preparations were hybridized in situ with probes labeled by nick translation, as previously described [32–33]. …”

Section: Methodsmentioning

confidence: 99%

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia

Minervini

Anelli

et al. 2016

Oncotarget

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“…hematopoietic cell proliferation and maturation (Abdel-Wahab et al, 2009;Albano et al, 2011;Chou et al, 2011;Euba et al, 2011;Figueroa et al, 2010;Pronier et al, 2011;Weissmann et al, 2011). Although Tet2 -/-mice appeared to develop normally overall, they displayed an abnormality in myeloid lineage differentiation and developed leukemia spontaneously Moran-Crusio et al, 2011;Quivoron et al, 2011).…”

Section: Tet Proteins In Postnatal Developmentmentioning

confidence: 99%

“…By contrast, TET2, although only recently identified, is the most studied member of the Tet family genes in MDS and other types of leukemia. It has been reported as one of the most frequently mutated genes in myeloid malignancies (Abdel-Wahab et al, 2009;Albano et al, 2011;Chou et al, 2011;Euba et al, 2011;Figueroa et al, 2010;Weissmann et al, 2011). Whereas some of the mutation sites in TET2 correspond to residues within the catalytic domain and could thus impair catalytic activity, many mutations appear unrelated to enzymatic activity (Ko et al, 2010).…”

Section: Tet Proteins In Postnatal Developmentmentioning

confidence: 99%

Tet family proteins and 5-hydroxymethylcytosine in development and disease

2012

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SummaryOver the past few decades, DNA methylation at the 5-position of cytosine (5-methylcytosine, 5mC) has emerged as an important epigenetic modification that plays essential roles in development, aging and disease. However, the mechanisms controlling 5mC dynamics remain elusive. Recent studies have shown that ten-eleven translocation (Tet) proteins can catalyze 5mC oxidation and generate 5mC derivatives, including 5-hydroxymethylcytosine (5hmC). The exciting discovery of these novel 5mC derivatives has begun to shed light on the dynamic nature of 5mC, and emerging evidence has shown that Tet family proteins and 5hmC are involved in normal development as well as in many diseases. In this Primer we provide an overview of the role of Tet family proteins and 5hmC in development and cancer.

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“…miR-138, down-regulated in CML cells but restored in response to imatinib treatment, was also recently found to target BCR-ABL [46]. Because it has been recently demonstrated that decreased TET2 gene expression associated with t(4;6;11) rearrangement may be involved in CML progression [47], it will be interesting to further analyse miR-22 expression profiling in CML patients.…”

Section: Mirnas In Myeloid Leukaemiamentioning

confidence: 99%

MicroRNAs in the pathogenesis of myelodysplastic syndromes and myeloid leukaemia

Song

Pandolfi²

2014

Current Opinion in Hematology

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Purpose of review This review highlights recent insights of the roles of microRNAs in pathogenesis of myeloid malignancies and tantalising prospects of microRNA therapy. Recent findings New roles for microRNAs in biological and disease processes are constantly being discovered. However, while great effort has been put into identifying and cataloguing aberrantly expressed microRNAs in leukaemia, very little is known about the functional consequences of their deregulation in myeloid malignancies. This review will discuss the significance of powerful oncogenic microRNAs such as miR-22 in self-renewal and transformation of hematopoietic stem cells, as well as their ability to induce epigenetic alterations in the pathogenesis of the stem cell disorder MDS and myeloid leukaemia. Summary Improved understanding of biological roles of microRNAs in pathogenesis of hematological malignancies will allow rational stratification of patients and provide new therapeutic entries for the treatment of MDS and leukaemia.

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Decreased TET2 gene expression during chronic myeloid leukemia progression

Cited by 30 publications

References 10 publications

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia

Tet family proteins and 5-hydroxymethylcytosine in development and disease

MicroRNAs in the pathogenesis of myelodysplastic syndromes and myeloid leukaemia

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