Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia
- Christian Hurtz1,2,8,
- Lai N. Chan1,2,8,
- Huimin Geng1,2,
- Erica Ballabio3,
- Gang Xiao1,2,
- Gauri Deb1,
- Haytham Khoury1,
- Chun-Wei Chen1,
- Scott A. Armstrong4,
- Jianjun Chen1,
- Patricia Ernst5,
- Ari Melnick6,7,
- Thomas Milne3 and
- Markus Müschen1,2
- 1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, California 91016, USA;
- 2Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
- 3Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom;
- 4Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 5Department of Pediatrics, University of Colorado, Denver, Colorado 80045, USA;
- 6Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
- 7Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
- Corresponding author: mmuschen{at}coh.org
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↵8 These authors equally contributed to this study.
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.327593.119.
- Received April 11, 2019.
- Accepted July 2, 2019.
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