SUZ12 is a candidate target of the non-canonical WNT pathway in the progression of chronic myeloid leukemia.
Polycomb proteins form multiprotein complexes that repress target genes by chromatin remodeling. In this work, we report that the SUZ12 polycomb gene is over-expressed in bone marrow samples of patients at the blastic phase of chronic myeloid leukemia. We also found a direct interaction between polycomb group genes and the WNT signaling pathway in chronic myeloid leukemia transformation. Electrophoretic mobility shift assay (EMSA), Chromatin immunoprecipitation assay (ChIP), and mass spectrometry assays identified noncanonical WNT pathway members, such as WNT5A and WNT11, bound to the SUZ12 promoter. Immunohistochemistry and immunofluorescence with WNT5A and WNT11 antibodies confirmed nuclear localization. Knockdown of WNTs 1, 5A, and 11 with RNAi approaches showed that WNT members are capable of activating SUZ12 transcription with varying promoter affinities. Finally, we suggest that SUZ12 is blocking cellular differentiation, as SUZ12 knockdown release differentiation programs in chronic myeloid blastic phase (CML-BP) transformed cell line.
Pizzatti
Luciana
L
Divisão de Laboratórios do CEMO, Instituto Nacional do Câncer, Rio de Janeiro, Brazil. pizzatti@inca.gov.br
Binato
Renata
R
Cofre
Jaime
J
Gomes
Bernadete E
BE
Dobbin
Jane
J
Haussmann
Maria Emilia
ME
D'Azambuja
Denise
D
Bouzas
Luis Fernando
LF
Abdelhay
Eliana
E
D000328:Adult; D001854:Bone Marrow Cells / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D015854:Up-Regulation; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
D002352:Carrier Proteins; D017931:DNA Primers; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D063151:Polycomb Repressive Complex 2