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Pontin Is a Critical Regulator for AML1-ETO-Induced Leukemia

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Leukemia (2014) 28, 1271–1279 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu ORIGINAL ARTICLE Pontin is a critical regulator for AML1-ETO-induced leukemia O Breig1, S Bras1, N Martinez Soria2, D Osman1,3, O Heidenreich2, M Haenlin1 and L Waltzer1 The oncogenic fusion protein AML1-ETO, also known as RUNX1-RUNX1T1 is generated by the t(8;21)(q22;q22) translocation, one of the most frequent chromosomal rearrangements in acute myeloid leukemia (AML). Identifying the genes that cooperate with or are required for the oncogenic activity of this chimeric transcription factor remains a major challenge. Our previous studies showed that Drosophila provides a genuine model to study how AML1-ETO promotes leukemia. Here, using an in vivo RNA interference screen for suppressors of AML1-ETO activity, we identified pontin/RUVBL1 as a gene required for AML1-ETO-induced lethality and blood cell proliferation in Drosophila. We further show that PONTIN inhibition strongly impaired the growth of human t(8;21) þ or AML1-ETO-expressing leukemic blood cells. Interestingly, AML1-ETO promoted the transcription of PONTIN. Moreover, transcriptome analysis in Kasumi-1 cells revealed a strong correlation between PONTIN and AML1-ETO gene signatures and demonstrated that PONTIN chiefly regulated the expression of genes implicated in cell cycle progression. Concordantly, PONTIN depletion inhibited leukemic self-renewal and caused cell cycle arrest. All together our data suggest that the upregulation of PONTIN by AML1-ETO participate in the oncogenic growth of t(8;21) cells. Leukemia (2014) 28, 1271–1279; doi:10.1038/leu.2013.376 Keywords: acute myeloid leukemia; AML1-ETO; PONTIN/RUVBL1; genetic screen; Drosophila INTRODUCTION Genetic screens in Drosophila have been successfully used to The development of hematopoietic malignancies is frequently identify genes implicated in different human pathologies 16 associated with the presence of recurrent chromosomal rearran- including cancers. Consequently, we have developed a gements that promote blood cell transformation by affecting key Drosophila model to study AML1-ETO. Indeed several aspects regulators of hematopoiesis. One of the most conspicuous is the of blood cell development have been conserved from Drosophila 17 t(8;21)(q22;q22) translocation, which is present in ±12% of all to humans. Notably, reminiscent of AML1 function in cases of acute myeloid leukemia (AML) and brings together AML1 mammals, the RUNX factor Lozenge (LZ) is required for the (also known as RUNX1) and ETO (also known as RUNX1T1).1,2 AML1 differentiation of crystal cells, one of the main Drosophila blood encodes a transcription factor of the RUNX family essential for cell lineages. AML1-ETO expression in this lineage antagonizes several steps of blood cell development and mutations or LZ function, induces a preleukemic-like phenotype characterized translocations affecting AML1 are associated with a variety of by the accumulation of crystal cell progenitors at the larval 18 malignant hemopathies.3 ETO encodes a transcriptional co- stage and causes lethality. Hence, this model provides a repressor that does not seem to participate in normal blood cell genetically tractable system to investigate the conserved basis of 18,19 development. The t(8;21) translocation results in the expression of leukemogenesis. the fusion protein AML1-ETO that comprises AML1 N-terminus, Using an in vivo RNA interference screen, we identified pontin/ including its conserved DNA-binding domain, and the almost RUVBL1 as a suppressor of AML1-ETO in Drosophila. PONTIN and its entire ETO protein. AML1-ETO can compete with AML1 for binding related partner REPTIN/RUVBL2 are conserved proteins of the to DNA and to some of its partners, while it multimerizes and AAA þ (adenosine triphosphatase associated with diverse cellular 20 interacts with other transcriptional regulators via its ETO moiety.4 activities) family. They are found in different complexes involved Therefore, AML1-ETO acts by interfering with the transcriptional in transcriptional regulation, DNA repair or ribonucleoprotein regulation of AML1 target genes but also by deregulating directly assembly. Moreover, several lines of evidence indicate that or indirectly the expression of other genes.5–7 PONTIN participates in cell growth and survival, notably in Cellular and animal models developed to explore how AML1-ETO hepatocellular carcinoma.21 However, its function in AML has promotes leukemia revealed that it acts as a dominant suppressor of not been studied. Our data show that knocking-down PONTIN AML1, impairs myeloid differentiation and promotes hematopoietic inhibits t(8;21) þ cells proliferation and that AML1-ETO expression progenitor self-renewal.8 However, AML1-ETO is not sufficient to sensitizes cells to PONTIN depletion. Moreover, AML1-ETO induce leukemia and secondary mutations are required for disease activates the expression of PONTIN and REPTIN. Genome-wide progression.9–11 Conversely, only a few targets or partners of AML1- expression profiling revealed that PONTIN gene signature ETO have been shown to be important for its oncogenic activity.12–15 correlates with that of AML1-ETO and indicates that PONTIN To gain further insight into t(8;21) leukemia and open new chiefly regulates cell cycle-associated genes. Furthermore, PONTIN avenues for therapeutic intervention, it is critical to delineate the appears required for Kasumi-1 clonogenic potential and cell cycle gene networks implicated in leukemogenesis. progression. We propose that PONTIN is a critical component for 1CNRS, CBD UMR5547, Universite´ de Toulouse, UPS, CBD (Centre de Biologie du De´veloppement), Baˆtiment 4R3, 118 route de Narbonne, Toulouse, France and 2Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, UK. Correspondence: Dr L Waltzer or Dr M Haenlin, Centre de Biologie du De´veloppement, CNRS, Universite´ de Toulouse, BA˜ btiment 4R3, 118 route de Narbonne, CNRS, CBD UMR5547, Toulouse 31062, France. E-mail: [email protected] or [email protected] 3Present address: Global Health Institute, School of Life Sciences, Station 19, EPFL, 1015 Lausanne, Switzerland. Received 8 November 2013; revised 5 December 2013; accepted 11 December 2013; accepted article preview online 17 December 2013; advance online publication, 14 January 2014 PONTIN function in AML1-ETO leukemia O Breig et al 1272 AML1-ETO-driven leukemic propagation and could be a potential were used. Detection was performed with Lumi-Light PLUS Western therapeutic target for t(8;21) AML. Blotting Substrate (Roche Applied Science) using Hyperfilm ECL (Amersham, GE Healthcare, Velizy-Villacoublay, France). MATERIALS AND METHODS mRNA isolation and real-time RT-PCR analysis Fly crosses and blood cells analyses Total RNA extraction was performed with RNeasy Kit (Qiagen). Reverse To identify suppressors of AML1-ETO-induced lethality, lz-GAL4, UAS-GFP; transcription (RT), and real-time quantitative PCR (qPCR) were performed as previously described using Bio-Rad CFX96 (Bio-Rad, Marnes-la-Coquette, UAS-aml1eto/CyO{tub-GAL80} virgins were crossed to males from individual 24 UAS-dsRNA stocks at 22 1C and were screened for non-CyO adults in their France) detection system. Primers used for qPCR amplification are shown progeny. All UAS-dsRNA stocks allowing the emergence of AML1-ETO- in Supplementary Table 6. expressing adults were re-tested twice and with independent UAS-dsRNA lines when available. The following lines were used to silence pontin: Cell growth, differentiation and clonogenic assays NIG4003R-1 and VDRC105408. LZ þ hemocyte number and differentiation Cells were transfected with siRNA two times (at days 0 and 3). Viable cell status were assessed as previously described.18 numbers were assessed every 3 days using Trypan blue exclusion assay. For differentiation assays, CD11b expression was monitored as marker for Cell culture myeloid differentiation 4 days after siRNA transfection. Cell staining was performed with allophycocyanin-conjugated anti-CD11b antibody (BD Kasumi-1, U937 and U937-AE (kindly provided by Dr M Ruthardt, Frankfurt, Biosciences, Le Pont de Claix, France) according to the manufacturer’s Germany) were cultured in RPMI 1640 (PAA Cell Culture Company, Les instructions. Cells were analyzed by flow cytometry (FACSCalibur, Becton Mureaux, France) plus 10% fetal calf serum (PAA Cell Culture Company). Dickinson, BD Biosciences). For colony formation assays, Kasumi-1 cells SKNO-1 cells were cultivated in RPMI 1640 containing 20% fetal calf serum were transfected with siRNA and 24 h post-transfection 2500 cells were and 10 ng/ml granulocyte macrophage colony-stimulating factor. Droso- plated in 250 ml semisolid medium (containing RPMI 1640, 20% fetal calf phila Kc167 cells were grown in Schneider’s medium (Invitrogen, Cergy serum and 0.56% methylcellulose) in 48-well plates. After 7 days of culture, Pontoise, France) supplemented with 10% fetal calf serum and 50 mgof clusters consisting of 420 cells were counted as colonies. penicillin–streptomycin (Invitrogen). Cell cycle analyses siRNA and dsRNA transfection Cellular DNA content was analyzed using DRAQ5 (Sigma-Aldrich) staining. The following small interfering RNA (siRNA) were purchased from Cells were fixed in 70% ethanol before being stained for 15 min with 2 mM 0 Eurogentec (Seraing, Belgium): AML1-ETO siRNA (5 - CCUCGAAAUCGUACU DRAQ5 and the relative DNA content per cell was measured using flow 0 22 0 GAGAAG-3 ), green fluorescent
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