MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia.

MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia. Haematologica. 2018 Feb 15;: Authors: Evensen NA, Madhusoodhan PP, Meyer J, Saliba J, Chowdhury A, Araten DJ, Nersting J, Bhatla T, Vincent TL, Teachey D, Hunger SP, Yang J, Schmiegelow K, Carroll WL Abstract Survival of children with relapsed acute lymphoblastic leukemia is poor and understanding mechanisms underlying resistance is essential in developing new therapy. Relapse-specific heterozygous deletions in MSH6, a crucial part of DNA Mismatch Repair, are frequently detected. Our aim was to determine whether MSH6 deletion results in a hypermutator phenotype associated with generation of secondary mutations involved in drug resistance or leads to a failure to initiate apoptosis directly in response to chemotherapeutic agents. We knocked down MSH6 in mismatch repair proficient cell lines (697 and UOCB1) and showed significant increases in IC50s to 6-Thioguanine & 6-Mercaptopurine (697: 26- and 9-fold; UOCB1: 5- and 8-fold) in vitro, as well as increased resistance to 6-Mercaptopurine treatment in vivo. No shift in IC50 was observed in deficient cells (Reh & RS4;11). 697 MSH6 knockdown resulted in increased DNA thioguanine nucleotide levels compared to non-targeted cells (3,070 versus 1,722 fmol/mg DNA) with no difference observed in mismatch repair deficient cells. Loss of MSH6 did not give rise ...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research