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Genes Dev. 2019 Sep 1;33(17-18):1265-1279. doi: 10.1101/gad.327593.119. Epub 2019 Aug 8.

Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia.

Author information

1
Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, California 91016, USA.
2
Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
3
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Department of Pediatrics, University of Colorado, Denver, Colorado 80045, USA.
6
Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
7
Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA.
#
Contributed equally

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.

KEYWORDS:

B cells; BCL6; BIM; MLL

PMID:
31395741
PMCID:
PMC6719625
[Available on 2020-03-01]
DOI:
10.1101/gad.327593.119
[Indexed for MEDLINE]

Publication types, MeSH terms, Substances, Grant support

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