Mismatch repair and the downstream target genes, PAX5 and Ikaros, in childhood acute lymphoblastic leukemia.
The mismatch repair (MMR) pathway is a post-replicative DNA repair process and MMR deficiency is a common feature of ALL cell lines. In this study we have investigated MMR deficiency in a large cohort of primary relapsed ALL (n=40) and investigated coding microsatellites (MS) of the lymphoid transcription factors, PAX5 and IKZF1 as downstream target genes. Only one patient showed MMR deficiency, as evidenced by microsatellite instability, which was acquired at relapse and was associated with reduced expression of both MLH1 and MSH2. Coding MS in candidate target genes including PAX5, IKZF1, BAX and TGFBRII were all wild type in this patient but the MMR-deficient cell line REH, was confirmed to have a coding MS in both PAX5 and TGFBRII. Whilst MMR deficiency is not highly prevalent in primary ALL, optimisation of the drug regimen to omit/replace thioguanines should be considered for children with MMR deficiency and/or reduced expression of key pathway components.
Best
Andrew
A
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Matheson
Elizabeth
E
Minto
Lynne
L
Hall
Andrew G
AG
Irving
Julie A E
JA
D000293:Adolescent; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007223:Infant; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051757:PAX5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
C494826:BAX protein, human; C497239:IKZF1 protein, human; D051757:PAX5 Transcription Factor; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D029961:Zebrafish Proteins; D051028:bcl-2-Associated X Protein; C497284:pax5 protein, zebrafish; D051740:Ikaros Transcription Factor; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II