CHECKPOINT KINASE 1 INHIBITION POTENTIATES APOPTOSIS AND INFLICTS MITOTIC FAILURE IN CLL-DERIVED MEC-1 CELL LINE

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216305%3A26620%2F16%3APU125842" target="_blank" >RIV/00216305:26620/16:PU125842 - isvavai.cz</a>

Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

CHECKPOINT KINASE 1 INHIBITION POTENTIATES APOPTOSIS AND INFLICTS MITOTIC FAILURE IN CLL-DERIVED MEC-1 CELL LINE

Original language description

Treatment options for TP53-mutated lymphoid tumors are very limited. In experimental models, TP53-mutated lymphomas were sensitive to direct inhibition of checkpoint kinase 1 (Chk1), a pivotal regulator of replication. We initially tested the potential of the highly specific Chk1 inhibitor SCH900776 to synergize with nucleoside analogs (NAs) fludarabine, cytarabine and gemcitabine in cell lines derived from B-cell malignancies. In p53-proficient NALM-6 cells, SCH900776 added to NAs enhanced signaling towards Chk1 (pSer317/pSer345), effectively blocked Chk1 activation (Ser296 autophosphorylation), increased replication stress (p53 and γ-H2AX accumulation) and temporarily potentiated apoptosis. In p53-defective MEC-1 cell line representing adverse chronic lymphocytic leukemia (CLL), Chk1 inhibition together with NAs led to enhanced and sustained replication stress and significantly potentiated apoptosis. Altogether, among 17 tested cell lines SCH900776 sensitized four of them to all three NAs. Focusing further on MEC-1 and co-treatment of SCH900776 with fludarabine, we disclosed chromosome pulverization in cells undergoing aberrant mitoses. SCH900776 also increased the effect of fludarabine in a proportion of primary CLL samples treated with pro-proliferative stimuli, including those with TP53 disruption. Finally, we observed a fludarabine potentiation by SCH900776 in a T-cell leukemia 1 (TCL1)-driven mouse model of CLL. Collectively, we have substantiated the significant potential of Chk1 inhibition in B-lymphoid cells.

Czech name

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Czech description

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Type

D - Article in proceedings

CEP classification

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OECD FORD branch

10306 - Optics (including laser optics and quantum optics)

Project

<a href="/en/project/ED1.1.00%2F02.0068" target="_blank" >ED1.1.00/02.0068: Central european institute of technology</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Article name in the collection

HAEMATOLOGICA

ISBN

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ISSN

0390-6078

e-ISSN

1592-8721

Number of pages

1

Pages from-to

425-425

Publisher name

FERRATA STORTI FOUNDATION, VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY

Place of publication

Neuveden

Event location

Copenhagen

Event date

Jun 9, 2016

Type of event by nationality

WRD - Celosvětová akce

UT code for WoS article

000379484601412