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Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

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Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia Germline RUNX1 variation and predisposition to childhood acute lymphoblastic leukemia Yizhen Li, … , Mignon L. Loh, Jun J. Yang J Clin Invest. 2021. https://doi.org/10.1172/JCI147898. Research In-Press Preview Genetics Oncology Graphical abstract Find the latest version: https://jci.me/147898/pdf 1 Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic 2 Leukemia 3 Yizhen Li, PhD1* , Wentao Yang, PhD1*, Meenakshi Devidas, PhD2, Stuart S. Winter, MD3, 4 Chimene Kesserwan, MD4, Wenjian Yang, PhD1, Kimberly P. Dunsmore, MD5, Colton Smith, 5 PhD1, Maoxiang Qian, PhD 6, Xujie Zhao, MS1, Ranran Zhang, MS1, Julie M. Gastier-Foster, PhD7, 6 Elizabeth A. Raetz, MD8, William L. Carroll, MD8, Chunliang Li, PhD9, Paul P. Liu10, Karen R. 7 Rabin, MD, PhD11, Takaomi Sanda12,13, Charles G. Mullighan, MBBS, MD14, Kim E. Nichols, MD15, 8 William E. Evans, PharmD1,16, Ching-Hon Pui, MD15,16, Stephen P. Hunger, MD17, David T. 9 Teachey18, MD, Mary V. Relling, PharmD1,16, Mignon L. Loh, MD 19, Jun J. Yang, PhD1, 15, 16, # 10 1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, 2Department of Global 11 Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, 3Children’s Minnesota Research Institute, 12 Children’s Minnesota, Minneapolis, MN, 4Center for Cancer Research, Genetics Branch, National Cancer Institute, 13 USA, 5Children’s Hematology and Oncology, Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, 14 VA, 6Children’s Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China, 7Baylor College of 15 Medicine and Texas Children’s Hospital, Houston, TX, 8Division of Pediatric Hematology and Oncology, Perlmutter 16 Cancer Center, New York University Langone Health, New York, 9Tumor Cell Biology, St. Jude Children’s Research 17 Hospital, Memphis, TN, 10Oncogenesis and Development Section, National Human Genome Research Institute, 18 National Institutes of Health, Bethesda, MD, USA, 11Texas Children’s Cancer and Hematology Centers, Baylor College 19 of Medicine, Houston, TX, 12Cancer Science Institute of Singapore, National University of Singapore, Singapore, 20 13Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 21 14Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, 15Department of Oncology, St. Jude 22 Children’s Research Hospital, Memphis, TN, 16Hematological Malignancies Program, St. Jude Children’s Research 23 Hospital, Memphis, TN, 17Department of Pediatrics and Center for Childhood Cancer Research, Children’s Hospital of 24 Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 18Division of 25 Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and 26 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19Department of Pediatrics, Benioff 27 Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 28 San Francisco, CA 29 *These authors contribute equally. 30 # Corresponding author: Jun J Yang, 262 Danny Thomas Place, MS313, Memphis, TN, 38105; 31 901-595-2517; [email protected] 32 Conflict of interest: The authors have no conflict of interest to declare. 1 33 Abstract 34 Genetic alterations in the RUNX1 gene are associated with benign and malignant blood disorders, 35 particularly of megakaryocyte and myeloid lineages. The role of RUNX1 in acute lymphoblastic 36 leukemia (ALL) is less clear, particularly how germline genetic variation influences the 37 predisposition to this type of leukemia. Sequencing 4,836 children with B-ALL and 1,354 cases of 38 T-ALL, we identified 31 and 18 germline RUNX1 variants, respectively. RUNX1 variants in B-ALL 39 consistently showed minimal damaging effects. By contrast, 6 T-ALL-related variants result in 40 drastic loss of RUNX1 activity as a transcription activator in vitro. Ectopic expression of dominant- 41 negative RUNX1 variants in human CD34+ cells repressed differentiation into erythroid, 42 megakaryocytes, and T cells, while promoting myeloid cell development. Chromatin 43 immunoprecipitation sequencing of T-ALL models showed distinctive patterns of RUNX1 binding 44 by variant proteins. Further whole genome sequencing identified JAK3 mutation as the most 45 frequent somatic genomic abnormality in T-ALL with germline RUNX1 variants. Co-introduction 46 of RUNX1 variant and JAK3 mutation in hematopoietic stem and progenitor cells in mice gave 47 rise to T-ALL with early T-cell precursor phenotype. Taken together, these results indicated that 48 RUNX1 is an important predisposition gene for T-ALL and pointed to novel biology of RUNX1- 49 mediated leukemogenesis in the lymphoid lineages. 2 50 Introduction 51 Acute lymphoid leukemia (ALL) is the most common cancer in children. The exact cause of ALL 52 is incompletely understood, although somatic genomic abnormalities are well documented 53 affecting a wide range of signaling pathways(1). There is also growing evidence of inherited 54 susceptibility to ALL. For example, common genetic polymorphisms in genes such as IKZF1(2), 55 ARID5B (3), CDKN2A(4), GATA3 (5, 6), CEBPE(7), PIP4K2A(8), and TCF3-PBX1(9) are 56 associated with the risk of ALL in an age- and subtype-dependent manner. On the other hand, 57 rare germline variants have been linked to familial predisposition to childhood ALL, particularly 58 notable in TP53(10), ETV6(11), and IKZF1(2, 9). These findings point to a strong genetic basis of 59 inter-individual variability in ALL risk. 60 The RUNX1 protein plays key roles in definitive hematopoiesis (12). RUNX1 functions as a 61 transcription factor by forming a heterodimer with core binding factor β (CBFβ). RUNX1 consists 62 of a Runt homology domain (RHD) responsible for DNA binding and cofactor interaction (13) and 63 the C-terminal transcriptional activation domain (TAD) that recruits co-activators and activates the 64 expression of RUNX1 target genes (14). RUNX1 germline variants are associated with familial 65 platelet disorder (FPD). Many patients with FPD develop leukemia later in life, predominately 66 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (15-18). Somatic RUNX1 67 mutations are also recurrent in B- and T-ALL; they mostly occur in the RHD and TAD domains 68 and more common in T-ALL(19, 20). RUNX1 mutations also are related to poor prognosis in T- 69 ALL(19) and particularly enriched in those with early T-cell precursor immunophenotype 70 (ETP)(21). The role of germline RUNX1 variants in the pathogenesis of ALL is much less known, 71 and their pattern, prevalence, and functional consequences in this lymphoid malignancy have not 72 been comprehensively investigated. 73 Here we report results from targeted germline sequencing of 6,190 children with B- or T-ALL 74 enrolled in frontline Children's Oncology Group (COG) and St. Jude Children's Research Hospital 75 (St. Jude) ALL trials. We observed a lineage-specific pattern of germline variation in the RUNX1 3 76 gene, with deleterious variants exclusively present in T-ALL patients. Furthermore, we 77 experimentally characterized RUNX1 variants for their effects on transcription factor activity, 78 subcellular localization, cofactor interaction, in vitro hematopoiesis, and genome wide RUNX1 79 binding profile. Finally, we examined the somatic genomic landscape of T-ALL arising from 80 RUNX1 germline variants and modeled RUNX1-mediated leukemogenesis in mouse models. 4 81 Results 82 Identification of germline RUNX1 variants in pediatric ALL 83 To comprehensively characterize inherited RUNX1 variations in ALL, we performed targeted 84 sequencing in germline DNA of 4,836 patients with newly diagnosed B-ALL and 1,354 patients 85 with T-ALL enrolled on COG and St. Jude frontline trials (Figure 1A and Table 1). We identified 86 31 unique variants in 61 B-ALL cases and 18 unique variants in 26 T-ALL cases. Seven of these 87 variants were found in both B- and T-ALL (Figure 1A and Table 1). 88 Of the 31 variants in B-ALL, 6 were not observed in the general population (Genome Aggregation 89 database, gnomAD, n = 15,496), 18 were rare with a maximum allele frequency of 0.00122%, 90 and the remaining 7 were considered common variants with allele frequency > 0.01% (Figure 1A 91 and Table 1). All variants in B-ALL except one were missense, most of which were in the C- 92 terminus distal to the DNA binding runt-homology domain (RHD, Figure 1B). Of the 18 variants 93 in T-ALL cases, 8 were absent in the gnomAD dataset, 5 were rare with a maximum allele 94 frequency of 0.00239%, and the remaining 5 were common variants (Figure 1A and Table 1). 95 Five of T-ALL-related variants were frameshift or nonsense, including 1) p.K117* and p.S141fs 96 which truncated both the RHD and the transcription activation domain (TAD, Figures 1B and S1) 97 and 2) p.Q213fs, p.R232fs, and p.Y287* that resulted in the loss of TAD only (Figure S1). Seven 98 missense and 1 in-frame deletion variants in T-ALL were distributed across RUNX1. This is 99 significantly different from the pattern of missense RUNX1 variants in FPD with associated 100 myeloid malignancy (FPDMM) (Figure 1C)(22), which are largely restricted to the DNA-binding 101 domain (p-value = 8.35 ×10-5, Fisher’s exact test). 102 103 Effects of RUNX1 variants on transcriptional regulation, cellular localization, and protein- 104 protein interaction 105 To understand how germline RUNX1 variants affect gene function, we first examined their 106 transcription activator activity using the luciferase reporter assay in Hela cells. With SPI1 as the 5 107 RUNX1 target gene (23), none of the germline variants identified in B-ALL showed a significant 108 impact on reporter gene transcription compared to the wildtype (WT) protein and therefore were 109 not studied further (Figure 2A and S1A).
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