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Deletion of MBD2 inhibits proliferation of chronic myeloid leukaemia blast phase cells.

ABSTRACT: Aberrant methylation of tumour suppressor genes is associated with the progression to a blast crisis in chronic myeloid leukaemia (CML). Methyl-CpG-binding domain protein 2 (MBD2) has been studied as a "reader" of DNA methylation in many cancers, but its role in CML is unclear. We constructed cell models of a homozygous deletion mutation of MBD2 using gene-editing technology in K562 cells and BV173 cells. Here, we demonstrated that the deletion of MBD2 inhibited cell proliferation capacity in vitro. MBD2 deletion also significantly inhibited K562 cell proliferation in a xenograft tumour model in vivo. Additionally, the JAK2/STAT3 signalling pathway, which is abnormally active in CML, was inhibited by MBD2 deletion, and MBD2 deletion could up-regulate the expression of SHP1. In conclusion, our findings suggest that MBD2 is a candidate therapeutic strategy for the CML blast phase.

SUBMITTER: Cheng L

PROVIDER: S-EPMC6067900 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Deletion of MBD2 inhibits proliferation of chronic myeloid leukaemia blast phase cells.

Cheng Ling L Tang Ying Y Chen Xing X Zhao Lei L Liu Songya S Ma Yanna Y Wang Na N Zhou Kuangguo K Zhou Jianfeng J Zhou Mi M

Cancer biology & therapy 20180419 8

Aberrant methylation of tumour suppressor genes is associated with the progression to a blast crisis in chronic myeloid leukaemia (CML). Methyl-CpG-binding domain protein 2 (MBD2) has been studied as a "reader" of DNA methylation in many cancers, but its role in CML is unclear. We constructed cell models of a homozygous deletion mutation of MBD2 using gene-editing technology in K562 cells and BV173 cells. Here, we demonstrated that the deletion of MBD2 inhibited cell proliferation capacity in vi ...[more]

PMID: 29565710

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Project description:BACKGROUND:Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. METHODS:We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868. FINDINGS:We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9–25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3–4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib. INTERPRETATION:Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting. FUNDING:MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.

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Deletion of MBD2 inhibits proliferation of chronic myeloid leukaemia blast phase cells.

Publications

Deletion of MBD2 inhibits proliferation of chronic myeloid leukaemia blast phase cells.

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