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SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia

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SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia Published OnlineFirst February 26, 2018; DOI: 10.1158/1541-7786.MCR-17-0493 Chromatin, Epigenetics and RNA Regulation Molecular Cancer Research SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia Shankha Subhra Chatterjee1, Mayukh Biswas1, Liberalis Debraj Boila1, Debasis Banerjee2, and Amitava Sengupta1 Abstract SWI/SNF is an evolutionarily conserved multi-subunit chroma- AML blasts, and loss-of-function studies confirmed transcriptional tin remodeling complex that regulates epigenetic architecture and regulation of Rac GTPase guanine nucleotide exchange factors cellular identity. Although SWI/SNF genes are altered in approx- (GEF) by SMARCB1. Mechanistically, loss of SMARCB1 increased D imately 25% of human malignancies, evidences showing their recruitment of SWI/SNF and associated histone acetyltransferases involvement in tumor cell–autonomous chromatin regulation (HAT) to target loci, thereby promoting H3K27Ac and gene and transcriptional plasticity are limiting. This study demonstrates expression. Together, SMARCB1 deficiency induced GEFs for Rac that human primary acute myeloid leukemia (AML) cells exhibit GTPase activation and augmented AML cell migration and sur- near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and vival. Collectively, these findings highlight tumor suppressor role D D SMARCD2 (BAF60B) associated with nucleation of SWI/SNF . of SMARCB1 and illustrate SWI/SNF function in maintaining an D SMARCC1 (BAF155), an intact core component of SWI/SNF , oncogenic gene expression program in AML. colocalized with H3K27Ac to target oncogenic loci in primary D AML cells. Interestingly, gene ontology (GO) term and pathway Implications: Loss of SMARCB1 in AML associates with SWI/SNF analysis suggested that SMARCC1 occupancy was enriched on nucleation, which in turn promotes Rac GTPase GEF expression, genes regulating Rac GTPase activation, cell trafficking, and AML- Rac activation, migration, and survival of AML cells, highlighting D associated transcriptional dysregulation. Transcriptome profiling SWI/SNF downstream signaling as important molecular regula- revealed that expression of these genes is upregulated in primary tor in AML. Mol Cancer Res; 16(5); 791–804. Ó2018 AACR. Introduction not always inform transcriptional dependencies embedded in tumorigenesis. SWI/SNF (BAF) chromatin remodelers are evolutionarily con- Emerging evidences indicate that SWI/SNF subunits critically served, large (2 MDa) multi-protein complexes, which utilize regulate murine hematopoiesis. Recent studies have shown that energy derived from ATP hydrolysis to mobilize nucleosomes (1). SMARCD2 mediates granulopoiesis through CEBPe-dependent SWI/SNF core components include SMARCB1 (BAF47, SNF5 or mechanism (5, 6). Actl6a (BAF53a) plays essential role in hemato- INI1), SMARCC1/SMARCC2 (BAF155 and BAF170), and one of poietic stem cell (HSC) function (7). Mutant allele of Arid1a the mutually exclusive ATPase subunits, SMARCA4 (BRG1) and (BAF250a) determines pool size of fetal liver HSC populations SMARCA2 (BRM). SWI/SNF complexes often include cell type– (8). In addition, SWI/SNF was also implicated in murine leuke- specific, lineage-restricted subunits, and play important roles in mia development. SMARCA4 was shown to regulate proliferation pluripotency and cellular reprogramming (1, 2). Cancer genome of murine leukemic cells (9, 10). SMARCB1 plays tumor sup- sequencing studies have identified SWI/SNF complexes as one of pressor role in several cancers, and frequent deletion of SMARCB1 the most commonly mutated (25%) chromatin modulators in is observed in chronic myeloid leukemia patients (11). Loss of human cancer (3, 4). However, mutational profiling alone may Smarcb1 in vivo leads to fully penetrant malignant rhabdoid tumors (12, 13). Rac GTPases belong to small Rho GTPase family and are 1 Stem Cell & Leukemia Lab, Cancer Biology & Inflammatory Disorder Division, involved in regulation of a diverse array of cellular functions CSIR-Indian Institute of Chemical Biology, Translational Research Unit of including cell proliferation, survival, adhesion, migration, actin Excellence (TRUE), Salt Lake, Kolkata, West Bengal, India. 2Clinical Hematology, Park Clinic, Gorky Terrace, Kolkata, West Bengal, India. assembly, and transcriptional activation (14, 15). Similar to Ras superfamily proteins, Rac GTPases cycle between inactive GDP- Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). bound and active GTP-bound conformations, regulated by spe- cific guanine nucleotide exchange factors (GEF), to transduce S.S. Chatterjee and M. Biswas contributed equally to this article. signals to effector proteins (14). Recent studies have suggested Corresponding Author: Amitava Sengupta, CSIR-Indian Institute of Chemical that Rac GTPases play integral roles in myeloid leukemia cell Biology, Kolkata 700091, India. Phone: 9133-2473-0492; Fax: 9133-2473-5197; homing, engraftment, survival, and trafficking within the bone E-mail: [email protected] marrow microenvironment (15–18). Attenuation of Rac GTPase doi: 10.1158/1541-7786.MCR-17-0493 signaling in synergy with Bcl-2 inhibition has been shown as a Ó2018 American Association for Cancer Research. modality for combination targeted therapy in MLL-AF9 leukemia www.aacrjournals.org 791 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst February 26, 2018; DOI: 10.1158/1541-7786.MCR-17-0493 Chatterjee et al. (19). Myeloid leukemia cells are characterized with elevated Rac and the integrity was assessed on a 0.8% Agarose Gel. Genomic GTP level; however, molecular regulation of Rac activation in DNA with OD260/OD280 >1.8 and OD260/OD230 1.3 was leukemia pathophysiology remains incompletely understood. used for microarray experiments. DNA was considered to be of Here we identify that in human primary acute myeloid good quality when a single clear band was seen when run against a leukemia (AML) cells, SMARCB1 deficiency associates with reference ladder. A total of 0.5 mg of DNA in 10.1 mL was taken into D nucleation of SWI/SNF . SMARCC1, an intact core component a microfuge tube and digestion master mix containing restriction D of SWI/SNF , colocalized with H3K27Ac to target tumor onco- enzymes (Alu I, 5U and Rsa I, 5U) was added. The samples were genic loci, including Rac GTPase GEFs,inAMLcells.Lossof incubated at 37C for 2 hours followed by heat inactivation of D SMARCB1 induced recruitment of SWI/SNF and associated enzymes at 65C for 20 minutes. Samples were labeled using histone acetyltransferases (HAT) to target GEFs for Rac GTPase Agilent sure tag DNA Labeling Kit (catalog no: 5190-3399). activation and promoted AML cell migration. Collectively, Control samples were labeled with Cy3 and test sample with these findings highlight tumor suppressor role of SMARCB1 Cy5. The labeled samples were cleaned up using Amicon Ultra D and illustrate SWI/SNF function in maintaining an oncogenic columns 30-kDa size exclusion filter. DNA yield and incorpo- gene expression program in AML. ration of labeled dye (specific activity) was measured using NanoDrop spectrophotometer. One micrograms each of Cy3- Materials and Methods and Cy5-labeled sample was added with human cot-1 DNA (catalog no. 5190-3393), Agilent aCGH/CoC Blocking agent (part Patient cohort number: 5188-6416), and hybridization buffer (part number: Human AML (n ¼ 67) bone marrow aspirates (1–2 mL each) 5188-6420). The labeled samples in above hybridization mix were obtained from Park Clinic, Kolkata from untreated, freshly were denatured at 95C for 3 minutes and were incubated at 37C diagnosed patients after written, informed consent according to for 30 minutes. The samples were then hybridized at 65C for 24 Institutional Human Ethics Committee (HEC) approval and hours. After hybridization, the slides were washed using Agilent following Indian Institute of Chemical Biology (CSIR-IICB) Insti- aCGH Wash Buffer1 (Agilent Technologies, part number 5188- tutional Review Board (IRB) set guidelines. Sample collection was 5221) at room temperature for 5 minutes and Agilent aCGH Wash part of routine diagnosis and the inclusion criterion for this study Buffer 2 (Agilent Technologies, part number 5188-5222) at 37C was histopathologic confirmation of bone marrow aspirates or for 1 minute. The slides were then washed with acetonitrile (part biopsies, karyotyping, and immunophenotypic analyses (20). number: A2094) for 10 seconds. The microarray slides were Bone marrow aspirates were also collected from age-matched scanned using Agilent Scanner (Agilent Technologies, part num- normal individuals (n ¼ 6) after informed consent, who turned ber G2600D). Image analysis was performed using Agilent Fea- out to be pathologically negative for AML (20). Individual case ture Extraction software, feature extracted raw data was analyzed information is presented in Supplementary Tables S1 and S2. using Agilent Genomic Workbench 7.0 software. The data were Umbilical cord blood samples (40 mL each) were obtained from normalized using Lowess normalization. Significant regions hav- Deb Shishu Nursing Home (Howrah, West Bengal, India) from ing amplification and deletions were identified among each of the term pregnancies after written, informed consent according to samples. Genomic view and chromosome view of the amplifica- CSIR-IICB HEC approval and following IRB set guidelines.
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