PKC? and PKM? are overexpressed in TCF3-rearranged paediatric acute lymphoblastic leukaemia and are associated with increased thiopurine sensitivity.

ABSTRACT: Both tumour suppressor and oncogenic functions have been ascribed to the atypical zeta isoform of protein kinase C (PKC?), whereas its constitutively active form PKM? is almost exclusively expressed in the brain where it has a role in long-term memory. Using primers unique for either isoform, we found that both PKC? and PKM? were expressed in a subset of paediatric acute lymphoblastic leukaemia (ALL) cases carrying a TCF3 (E2A) chromosomal rearrangement. Combined PKC? and PKM? (PKC/M?) protein as well as phosphorylation levels were elevated in ALL cases, especially TCF3-rearranged precursor B-ALL cases, compared with normal bone marrow (P<0.01). Furthermore, high PKC/M? expression in primary ALL cells was associated with increased sensitivity to 6-thioguanine and 6-mercaptopurine (P<0.01), thiopurines used in ALL treatment. PKC? is believed to stabilize mismatch-repair protein MSH2, facilitating thiopurine responsiveness in T-ALL. However, PKC/M? knockdown in a TCF3-rearranged cell line model decreased MSH2 expression but did not induce thiopurine resistance, indicative that the link between high PKC/M? levels and thiopurine sensitivity in paediatric precursor B-ALL is not directly causal. Collectively, our data indicate that thiopurine treatment may be effective, especially in paediatric TCF3-rearranged ALL and other patients with a high expression of PKC/M?.

SUBMITTER: Hartsink-Segers SA 

PROVIDER: S-EPMC4320296 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature