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Cancer Cell ; 35(4): 649-663.e10, 2019 04 15.
Article in English | MEDLINE | ID: mdl-30991025

ABSTRACT

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1+ B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1+ B-ALL.


Subject(s)
Fusion Proteins, bcr-abl/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Wnt Signaling Pathway , gamma Catenin/metabolism , Animals , Fusion Proteins, bcr-abl/genetics , Gene Expression Regulation, Leukemic , Humans , K562 Cells , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Survivin/genetics , Survivin/metabolism , beta Catenin/genetics , beta Catenin/metabolism , gamma Catenin/genetics
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