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Chemogenomic Landscape of RUNX1-Mutated AML Reveals Importance of RUNX1 Allele Dosage in Genetics and Glucocorticoid Sensitivity

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Chemogenomic Landscape of RUNX1-Mutated AML Reveals Importance of RUNX1 Allele Dosage in Genetics and Glucocorticoid Sensitivity Author Manuscript Published OnlineFirst on August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity Laura Simon1, Vincent-Philippe Lavallée1,2, Marie-Eve Bordeleau1, Jana Krosl1, Irène Baccelli1, Geneviève Boucher1, Bernhard Lehnertz1, Jalila Chagraoui1, Tara MacRae1, Réjean Ruel1, Yves Chantigny1, Sébastien Lemieux1,3, Anne Marinier1,4, Josée Hébert1,2,5,6,* and Guy Sauvageau1,2,5,6,*. 1 The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, H3T 1J4, Canada. 2 Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, Québec, H1T 2M4, Canada. 3 Department of Computer Science and Operations Research, Université de Montréal, Montréal, Canada. 4 Department of Chemistry, Université de Montréal, Montréal, Canada. 5 Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, Canada. 6 Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Canada. *Corresponding Authors Running title: RUNX1 dosage in genetics and GC sensitivity of RUNX1mut AML Keywords: Acute Myeloid Leukemia; RUNX1; RNA-sequencing; chemical screening; glucocorticoids. Additional information Financial support: 1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. L.S. is supported by the IRIC Members Ph.D. Awards and the Faculté de Médecine recruitment scholarship (Université de Montréal), and the Cole Foundation. V.-P.L. is supported by a fellowship from the Cole Foundation. This work was supported in part by the Government of Canada through Genome Canada and the Ministère de l’économie, de l’innovation et des exportations du Québec through Génome Québec and the Fonds de partenariat pour un Québec innovant et en santé, with supplementary funds from AmorChem and, through grants awarded to G.S., J.H., A.M. and S.L. The work was also supported by a CCSRI impact grant to G.S. G.S. and J.H. are recipients of research chairs from the Canada Research Chair program and Industrielle-Alliance (Université de Montréal), respectively. The BCLQ is supported by grants from the Cancer Research Network of the Fonds de recherche du Québec-Santé (FRQS). Corresponding authors’ information: Guy Sauvageau, Institute for Research in Immunology and Cancer (IRIC), P.O. Box 6128, Downtown Station, Montreal, QC, Canada, H3C 3J7. E-mail: [email protected], phone: (514) 343-7134, fax: (514) 343-5839, and, Josée Hébert, Quebec Leukemia Cell Bank, Research Centre, Maisonneuve- Rosemont Hospital, 5415 L'Assomption Blvd, Montreal, QC, Canada, H1T 2M4. E-mail: [email protected], phone: (514) 252-3404, fax: (514) 254-5094. Conflict of interest: The authors declare no competing financial interests. Word count: 4,977 words Figures: 6 Tables: 6 Supplementary Figures: 8 2 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of translational relevance This study characterized the effect of RUNX1 allele dosage on the gene expression profile and glucocorticoid sensitivity of primary RUNX1mut AML specimens. Our findings suggest a new role for RUNX1 in the glucocorticoid response and support the rationale to evaluate the addition of glucocorticoids in preclinical models of RUNX1mut AML. 3 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: RUNX1-mutated (RUNX1mut) Acute Myeloid Leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Towards this goal, we further dissected the mutational spectrum and gene expression profile of RUNX1mut AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup. Experimental design: RNA-sequencing of 47 RUNX1mut primary AML specimens was performed and sequencing results were compared to those of RUNX1 wild-type samples. Chemical screens were also conducted using RUNX1mut specimens to identify compounds selectively affecting the viability of RUNX1mut AML. Results: We show that samples with no remaining RUNX1 wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most RUNX1mut specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the Glucocorticoid Receptor (GR). We observed that specimens harboring RUNX1 mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that co-associating mutations as well as that GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating RUNX1 expression in human AML cells. Conclusion: Our findings show the profound impact of RUNX1 allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. 4 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction RUNX1 is a master regulator of definitive hematopoiesis where it regulates the differentiation of myeloid, megakaryocytic and lymphocytic lineage progenitors (1,2). RUNX1 is part of the core binding factor (CBF) transcriptional complex, and its transcriptional activity is dependent on the recruitment of its heterodimeric partner, CBFB. RUNX1 contains a RUNT domain at its N-terminus that is responsible for both DNA binding and protein heterodimerization (3). The C- terminal region of the protein encompasses domains for nuclear localization and regulation of DNA binding (4), as well as for the interaction with lineage specific transcription factors, transcriptional coactivators and corepressors. Anomalies involving the RUNX1 gene or its partner CBFB have been implicated in the pathogenesis of subsets of human myeloid and lymphoblastic leukemias (5). The RUNX1 and CBFB genes are involved in the t(8;21)(q22;q22) and inv(16)(p13.1q22) chromosomal rearrangements, respectively, and these entities constitute the CBF Acute Myeloid Leukemia (AML) subgroup (6,7). Prognosis is favorable for patients carrying these cytogenetic anomalies when compared with other AML subtypes (8). In addition to chromosomal rearrangements, mutations in the RUNX1 gene are also found in myelodysplastic syndrome (MDS) and in 10-21% of AMLs where they are associated with French-American-British (FAB) M0 morphology (9–11). In contrast to CBF AMLs, RUNX1mut AMLs are associated with adverse outcome (11–17). In a large proportion of cases, RUNX1mut AMLs harbor normal karyotype or non-complex chromosomal imbalances, with a frequent association with trisomy 13 (12–15). RUNX1 mutations are also generally mutually exclusive of recurrent translocations in AML, and mutational analyses using targeted approaches revealed that RUNX1 mutations co-occur with mutations in epigenetic modifiers, such as ASXL1, splicing factors, STAG2, BCOR and PHF6 (14,17). Microarray analysis has been used to derive a RUNX1 mutation-associated gene expression signature (17), however a complete assessment of the mutational and gene expression landscape of RUNX1mut AML is lacking. 5 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Two types of mutations in RUNX1 have been described in AML: missense mutations found in the RUNT domain, and nonsense or frameshift mutations distributed throughout the entire gene. Some frameshift mutations located in the C-terminal region produce elongated versions of the protein with intact DNA binding activity that retain the ability to heterodimerize with CBFB and that are believed to act as dominant negatives (10,12,15,18). Approximately 30% of RUNX1 mutations occur in combination (i.e. double heterozygosity) or are associated with a loss of heterozygosity, both of which lead to a complete loss of wild-type RUNX1 in these leukemias (15). In line with this, it has been proposed that the greater the extent of RUNX1 inactivation in hematopoietic cells,
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