title: PKCζ and PKMζ 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 (PKCζ), whereas its constitutively active form PKMζ 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 PKCζ and PKMζ were expressed in a subset of paediatric acute lymphoblastic leukaemia (ALL) cases carrying a TCF3 (E2A) chromosomal rearrangement. Combined PKCζ and PKMζ (PKC/Mζ) 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/Mζ expression in primary ALL cells was associated with increased sensitivity to 6-thioguanine and 6-mercaptopurine (P<0.01), thiopurines used in ALL treatment. PKCζ is believed to stabilize mismatch-repair protein MSH2, facilitating thiopurine responsiveness in T-ALL. However, PKC/Mζ knockdown in a TCF3-rearranged cell line model decreased MSH2 expression but did not induce thiopurine resistance, indicative that the link between high PKC/Mζ 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/Mζ.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Hartsink-Segers
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Beaudoin
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M W J
authors.initials: MW
authors.lastname: Luijendijk
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Exalto
authors.affiliation: 1] Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands [2] Prinses Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: Den Boer
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology; D015122:Mercaptopurine / Q000737:chemistry*; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D013866:Thioguanine / Q000737:chemistry; D000099221:Protein Kinase C zeta
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007527:Isoenzymes; D015122:Mercaptopurine; D011493:Protein Kinase C; D013866:Thioguanine; D000099221:Protein Kinase C zeta; C407909:TCF3 protein, human