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The Polycomb Complex PRC2 Supports Aberrant Self-Renewal in a Mouse Model of MLL-AF9;Nrasg12d Acute Myeloid Leukemia

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The Polycomb Complex PRC2 Supports Aberrant Self-Renewal in a Mouse Model of MLL-AF9;Nrasg12d Acute Myeloid Leukemia Oncogene (2013) 32, 930 --938 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc SHORT COMMUNICATION The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia J Shi1,2,7, E Wang1,7, J Zuber1,3, A Rappaport1,4, M Taylor1, C Johns1, SW Lowe1,5,6 and CR Vakoc1 The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein mixed lineage leukemia (MLL) can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that requires multiple epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb repressive complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12 or Ezh1/Ezh2 led to proliferation arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer. Oncogene (2013) 32, 930--938; doi:10.1038/onc.2012.110; published online 2 April 2012 Keywords: chromatin; leukemia; epigenetics; MLL; PRC2 INTRODUCTION direct repression of pro-differentiation genes.12 --14 Additionally, Cellular identity in multicellular organisms is reinforced by master- several lines of evidence link the function of PRC2 to the regulatory transcription factors in concert with chromatin modify- pathogenesis of human cancer. Ezh2 is overexpressed in many ing activities. A major epigenetic regulatory axis maintaining the different malignancies and mutations that elevate its tri-methyl- ‘ON’ or ‘OFF’ state of transcription is composed of the Trithorax and transferase activity are found in subtypes of lymphoma, together 5,15 --17 Polycomb groups of chromatin regulators, respectively (for review suggesting a pro-tumorigenic role for this complex. How- see1,2). First discovered in Drosophila based on their antagonistic ever, Ezh2 loss-of-function mutations have also been observed in regulation of homeotic phenotypes,3,4 Trithorax and Polycomb myelodysplastic syndrome (MDS), suggesting a tumor suppressor 18,19 group proteins have emerged as key regulators of transcriptional function in certain cellular contexts. Interestingly, Ezh2 loss-of- programs underlying embryonic development, tissue homeostasis function mutations are rarely observed in primary acute myeloid and the pathogenesis of several human diseases, including leukemia (AML), suggesting that a role for PRC2 in myeloid cancer cancer.5 Trithorax and Polycomb group proteins possess diverse might be highly dependent on cellular and genetic context (Ross regulatory activities directed toward chromatin, including lysine Levine, personal communication). methyltransferase, ubiquitin ligase, chromatin remodeling ATPase, In mammals, a major class of Trithorax-group genes belongs to as well as a host of histone-binding modules.1,2 the mixed lineage leukemia (MLL) subfamily. MLL (also known as Polycomb repressive complex 2 (PRC2) mediates gene silencing MLL1) encodes a histone H3K4 methyltransferase essential for through catalysis of histone H3K27 methylation.6--8 PRC2 is hematopoietic development through maintenance of transcrip- 20 minimally comprised of two essential non-catalytic subunits, Eed tion of specific target genes, most notably HOX clusters. Mutant and Suz12, as well as one of two SET domain containing forms of MLL also act as potent oncogenes in AML pathogenesis, methyltransferase subunits, Ezh1 or Ezh2.6--9 Recruitment of which are generally associated with chemotherapy-resistant 21 PRC2 generally occurs at CpG-rich promoter sequences in the disease (reviewed in Krivtsov and Armstrong ). MLL can often genome, mediated through an assortment of protein--protein and be mutated via chromosomal translocation, where the N-terminal protein--RNA interactions to establish localized domains of H3K27 fragment of MLL is fused to the C-terminus of one of over 50 methylation.10,11 This histone mark serves as a docking site for known partner genes, with AF9 being the most common in AML.22 other Polycomb complexes, which exert a repressive effect on MLL-AF9 acts in a gain-of-function manner via aberrant recruit- transcription.6 A key function of PRC2 in mammals is to regulate ment of AF9-interacting proteins to normal MLL target genes, stem cell function, where it can promote self-renewal through resulting in transcriptional hyperactivation. The biological con- 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; 2Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY, USA; 3Research Institute of Molecular Pathology (IMP), Vienna, Austria; 4Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; 5Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA and 6Howard Hughes Medical Institute, Cold Spring Harbor, NY, USA. 7These authors contributed equally to this work. Correspondence: Dr CR Vakoc or Dr SW Lowe, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. E-mail: [email protected] or [email protected] Received 4 January 2012; revised 2 February 2012; accepted 23 February 2012; published online 2 April 2012 PRC2 supports aberrant self-renewal in MLL-leukemia J Shi et al 931 sequence of MLL-AF9 expression is a blockade of myeloid signaling pathway (e.g., NRASG12D), is thought to be sufficient for maturation and an enduring state of self-renewal. Coupling of leukemic transformation.23,24 As one of the only known examples MLL-AF9 expression with activating mutations in the MAP kinase- of a proto-oncogene chromatin regulator, MLL-fusion leukemia Polr2b 64 50 Myc Pcna 30 Men1 32 Rpl15 40 Eed Rpa3 cells 16 Kdm1a 20 Rpa1 30 G12D Suz12 8 4 20 10 2 10 MLL-AF9;Nras Relative growth inhibition Ren Relative G1E growth inhibition 1 Relative EML growth inhibition 0 0 0.5 0.5 1 2 4 8 16 32 64 Relative growth inhibition Ren.713 Ren.713 Eed.1820 Rpa3.457Myc.2105 Eed.1820 Rpa3.457Myc.2105 Men1.2310 Men1.2310 32D myeloblast cells Suz12.1676Kdm1a.2435 Suz12.1676Kdm1a.2435 25 15 50 Leukemia Leukemia Leukemia 20 32D 32D 40 32D 10 15 30 10 20 5 5 10 Relative growth inhibition Relative growth inhibition Relative growth inhibition 0 0 0 Ren. Eed. Eed. Eed. Eed. Eed. Ren. Suz12. Suz12. Suz12. Suz12. Ren. Men1. Men1. Men1. Men1. 713 949 710 1397 1083 1820 713 3979 909 1842 1676 713 219 1457 2707 2310 1.0 1.0 1.0 0.8 0.8 0.8 RNA level RNA level RNA level 0.6 0.6 0.6 Eed 0.4 0.4 0.4 Men1 Suz12 0.2 0.2 0.2 Relative Relative 0.0 Relative 0.0 0.0 Ren. Eed. Eed. Eed. Eed. Eed. Ren. Suz12. Suz12. Suz12. Suz12. Ren. Men1. Men1. Men1. Men1. 713 949 710 1397 1083 1820 713 3979 909 1842 1676 713 219 1457 2707 2310 Ren. Eed. 1.0 1st infection 2nd infection 713 9491397 710 1083 1820 LMN-mCherry LMN-GFP αH3K27me3 Ren.713 Ren.713 αH3 Ezh1.4105 Ren.713 0.5 Ren.713 Ezh2.781 Ezh1.4105 Ezh2.781 Suz12. Relative mCherry+ Ren. GFP+% (normalized) 713 3979 909 1842 1676 αH3K27me3 0.0 αH3 1 24681012 Days post-infection Figure 1. RNAi screen identifies Eed and Suz12 as unique requirements for growth of MLL-AF9;NrasG12D leukemia. (a) Scatter-plot comparison of the relative growth inhibition conferred by LMN-shRNAs in MLL-AF9;NrasG12D leukemia and 32D myeloblasts. All shRNAs evaluated were identified from a pooled negative-selection shRNA screen reported previously.25 MLL-AF9;NrasG12D leukemia or 32D myeloblasts were transduced with individual LMN-shRNA vectors (MSCV-miR30-shRNA-PGK-NeoR-IRES-GFP), followed by measurement of the GFP-per- centage at day 2 and day 12 postinfection using a Guava Easycyte (Millipore, Billerica, MA, USA). Growth inhibition was calculated as the ratio of the GFP percentage measured at day 2 to day 12 of partially transduced cell populations. As leukemia and 32D cells grow at comparable rates in vitro (Supplementary Figure 1), relative GFP depletion is a suitable assay for comparing growth effects in each line. Control shRNAs are indicated with white circles. Box indicates shRNAs with leukemia-specific growth inhibition. (b-- f) Relative growth inhibition conferred by indicated LMN shRNAs in EML, G1E, leukemia and 32D cell lines, calculated as in a (n ¼ 3). (g-- i) Quantitative reverse transcription PCR measuring knockdown efficiency in 32D myeloblast cells following transduction with LMN-shRNAs and selection with G418. Measurements were normalized to Gapdh, with the relative mRNA level in the cells with control Ren shRNA set to 1 (n ¼ 3). (j) Relative change double- transduced cell percentage following cotransduction transduced with indicated LMN-shRNAs linked to either GFP or mCherry reporters. The results were normalized to the GFP þ /mCherry þ percentage measured at day 1, set to 1 (n ¼ 3). (k, l) H3K27me3 western blotting of acid extracted histones prepared from 32D cells transduced with the indicated LMN-shRNA following G418 selection. The levels of total histone H3 serve as a loading control. A representative experiment of three replicates is shown. All error bars represent s.e.m. & 2013 Macmillan Publishers Limited Oncogene (2013) 930 --938 PRC2 supports aberrant self-renewal in MLL-leukemia J Shi et al 932 represents a paradigm for understanding causality between disease.
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