Publication detail

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

ZEMANOVÁ, J. HYLSE, O. ČOLLÁKOVÁ, J. VESELÝ, P. OLTOVÁ, A. PARUCH, K. TRBUŠEK, M.

Original Title

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

Type

conference paper

Language

English

Original Abstract

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.

Keywords

checkpoint kinase 1/Chk1, SCH900776, nucleoside analogs, chronic lymphocytic leukemia, TP53

Authors

ZEMANOVÁ, J.; HYLSE, O.; ČOLLÁKOVÁ, J.; VESELÝ, P.; OLTOVÁ, A.; PARUCH, K.; TRBUŠEK, M.

Released

9. 6. 2016

Publisher

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

ISBN

0390-6078

Periodical

Haematologica-The Hematology Journal

Year of study

101

State

Republic of Italy

Pages from

425

Pages to

425

Pages count

1

URL

http://cel.webofknowledge.com/InboundService.do?mode=FullRecord&customersID=tsmetrics&IsProductCode=Yes&product=CEL&Init=Yes&Func=Frame&action=retrieve&SrcApp=tsm_test&SrcAuth=tsmetrics&SID=E6NHlmMlNVklyzTVxYb&UT=WOS%3A000379484601412

BibTex

@inproceedings{BUT142512,
  author="Jana {Zemanová} and Ondřej {Hylse} and Jana {Čolláková} and Pavel {Veselý} and Alexandra {Oltová} and Kamil {Paruch} and Martin {Trbušek}",
  title="CHECKPOINT KINASE 1 INHIBITION POTENTIATES APOPTOSIS AND INFLICTS MITOTIC FAILURE IN CLL-DERIVED MEC-1 CELL LINE",
  booktitle="HAEMATOLOGICA",
  year="2016",
  journal="Haematologica-The Hematology Journal",
  volume="101",
  pages="425--425",
  publisher="FERRATA STORTI FOUNDATION, VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY",
  issn="0390-6078",
  url="http://cel.webofknowledge.com/InboundService.do?mode=FullRecord&customersID=tsmetrics&IsProductCode=Yes&product=CEL&Init=Yes&Func=Frame&action=retrieve&SrcApp=tsm_test&SrcAuth=tsmetrics&SID=E6NHlmMlNVklyzTVxYb&UT=WOS%3A000379484601412"
}