1. Rationale for targeting BCL6 in MLL -rearranged acute lymphoblastic leukemia.
- Author
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Hurtz C, Chan LN, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Chen CW, Armstrong SA, Chen J, Ernst P, Melnick A, Milne T, and Müschen M
- Subjects
- Animals, Biomarkers, Tumor genetics, Cell Survival genetics, Cells, Cultured, Gene Deletion, Gene Targeting, Humans, Mice, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Prognosis, Promoter Regions, Genetic genetics, Gene Expression Regulation, Leukemic, Myeloid-Lymphoid Leukemia Protein genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma physiopathology, Proto-Oncogene Proteins c-bcl-6 genetics, Proto-Oncogene Proteins c-bcl-6 metabolism
- Abstract
Chromosomal rearrangements of the mixed lineage leukemia ( MLL ) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL- rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL- rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL- rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL., (© 2019 Hurtz et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2019
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