HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we r...

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Bibliographic Details
Published in:	Leukemia Vol. 32; no. 1; pp. 49 - 60
Main Authors:	Tharkar-Promod, S, Johnson, D P, Bennett, S E, Dennis, E M, Banowsky, B G, Jones, S S, Shearstone, J R, Quayle, S N, Min, C, Jarpe, M, Mosbruger, T, Pomicter, A D, Miles, R R, Chen, W Y, Bhalla, K N, Zweidler-McKay, P A, Shrieve, D C, Deininger, M W, Chandrasekharan, M B, Bhaskara, S
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-01-2018 Nature Publishing Group
Subjects:	13/106 13/31 13/51 38/1 38/15 38/91 631/67/1990 64/60 692/699/1541 82/51 82/58 82/80 Acute lymphoblastic leukemia Acute lymphocytic leukemia Addictions Animal models Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology BCR protein Cancer Research Cell Line, Tumor Chemotherapy Chromatin Critical Care Medicine Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded - drug effects DNA damage DNA repair DNA Repair - drug effects Dosage and administration Double-strand break repair Doxorubicin Doxorubicin - administration & dosage Drug therapy Fusion Proteins, bcr-abl - metabolism Gene silencing Genetic aspects Hematology Histone Deacetylase 1 - antagonists & inhibitors Histone Deacetylase 2 - antagonists & inhibitors Humans Inhibition Inhibitors Intensive Internal Medicine Leukemia Lymphatic leukemia Lymphocytes B Mass spectrometry Mass spectroscopy Medical prognosis Medicine Medicine & Public Health Mice MRE11 protein Oncology Original original-article Philadelphia chromosome Philadelphia Chromosome - drug effects Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Proteomes Repair Signaling Xenografts
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Summary:	Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11–Rad51–DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis )) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair ‘addiction’ and provide an effective therapeutic option for Ph+ B-cell precursor ALL.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	0887-6924 1476-5551 1476-5551
DOI:	10.1038/leu.2017.174