DOCSLIB.ORG

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

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemogenomic Landscape of RUNX1-Mutated AML Reveals Importance of RUNX1 Allele Dosage in Genetics and Glucocorticoid Sensitivity Published OnlineFirst August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Cancer Therapy: Preclinical Clinical Cancer Research Chemogenomic Landscape of RUNX1-mutated AML Reveals Importance of RUNX1 Allele Dosage in Genetics and Glucocorticoid Sensitivity Laura Simon1, Vincent-Philippe Lavallee 1,2, Marie-Eve Bordeleau1, Jana Krosl1, Irene Baccelli1, Genevieve Boucher1, Bernhard Lehnertz1, Jalila Chagraoui1, Tara MacRae1,Rejean Ruel1, Yves Chantigny1,Sebastien Lemieux1,3, Anne Marinier1,4, Josee Hebert 1,2,5,6, and Guy Sauvageau1,2,5,6 Abstract Purpose: RUNX1-mutated (RUNX1mut) acute myeloid leuke- more homogeneous gene expression profile. Chemical screening mia (AML) is associated with adverse outcome, highlighting the revealed that most RUNX1mut specimens are sensitive to gluco- urgent need for a better genetic characterization of this AML corticoids (GCs) and we confirmed that GCs inhibit AML cell subgroup and for the design of efficient therapeutic strategies for proliferation through their interaction with the glucocorticoid this disease. Toward this goal, we further dissected the mutational receptor (GR). We observed that specimens harboring RUNX1 spectrum and gene expression profile of RUNX1mut AML and mutations expected to result in low residual RUNX1 activity are correlated these results to drug sensitivity to identify novel com- most sensitive to GCs, and that coassociating mutations as well as pounds targeting this AML subgroup. GR levels contribute to GC sensitivity. Accordingly, acquired Experimental Design: RNA-sequencing of 47 RUNX1mut pri- glucocorticoid sensitivity was achieved by negatively regulating mary AML specimens was performed and sequencing results were RUNX1 expression in human AML cells. compared to those of RUNX1 wild-type samples. Chemical screens Conclusions: Our findings show the profound impact of were also conducted using RUNX1mut specimens to identify com- RUNX1 allele dosage on gene expression profile and glucocorti- pounds selectively affecting the viability of RUNX1mut AML. coid sensitivity in AML, thereby opening opportunities for pre- Results: We show that samples with no remaining RUNX1 clinical testing which may lead to drug repurposing and improved wild-type allele are clinically and genetically distinct and display a disease characterization. Clin Cancer Res; 1–13. Ó2017 AACR. Introduction heterodimerization (3). The C-terminal region of the protein encompasses domains for nuclear localization and regulation of RUNX1 is a master regulator of definitive hematopoiesis where DNA binding (4), as well as for the interaction with lineage- it regulates the differentiation of myeloid, megakaryocytic, and specific transcription factors, transcriptional coactivators, and lymphocytic lineage progenitors (1, 2). RUNX1 is part of the core corepressors. binding factor (CBF) transcriptional complex, and its transcrip- Anomalies involving the RUNX1 gene or its partner CBFB have tional activity is dependent on the recruitment of its heterodi- been implicated in the pathogenesis of subsets of human myeloid meric partner, CBFB. RUNX1 contains a RUNT domain at its N- and lymphoblastic leukemias (5). The RUNX1 and CBFB genes are terminus that is responsible for both DNA binding and protein involved in the t(8;21)(q22;q22) and inv(16)(p13.1q22) chro- mosomal rearrangements, respectively, and these entities consti- tute the CBF acute myeloid leukemia (AML) subgroup (6, 7). 1The Leucegene Project at Institute for Research in Immunology and Cancer, Universite de Montreal, Montreal, Quebec, Canada. 2Division of Hematology, Prognosis is favorable for patients carrying these cytogenetic Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. 3Department of anomalies when compared with other AML subtypes (8). In Computer Science and Operations Research, Universite de Montreal, Montreal, addition to chromosomal rearrangements, mutations in the Canada. 4Department of Chemistry, Universite de Montreal, Montreal, Canada. RUNX1 gene are also found in myelodysplastic syndrome (MDS) 5Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, and in 10%–21% of AMLs where they are associated with French- 6 Canada. Department of Medicine, Faculty of Medicine, Universite de Montreal, American-British (FAB) M0 morphology (9–11). In contrast to Montreal, Canada. CBF AMLs, RUNX1mut AMLs are associated with adverse outcome Note: Supplementary data for this article are available at Clinical Cancer (11–17). In a large proportion of cases, RUNX1mut AMLs harbor Research Online (http://clincancerres.aacrjournals.org/). normal karyotype or noncomplex chromosomal imbalances, Corresponding Authors: Guy Sauvageau, Institute for Research in Immunology with a frequent association with trisomy 13 (12–15). RUNX1 and Cancer (IRIC), P.O. Box 6128, Downtown Station, Montreal, Quebec H3C 3J7, mutations are also generally mutually exclusive of recurrent Canada. Phone: 514-343-7134; Fax: 514-343-5839; E-mail: translocations in AML, and mutational analyses using targeted [email protected]; and Josee Hebert, [email protected] approaches revealed that RUNX1 mutations cooccur with muta- doi: 10.1158/1078-0432.CCR-17-1259 tions in epigenetic modifiers, such as ASXL1, splicing factors, Ó2017 American Association for Cancer Research. STAG2, BCOR, and PHF6 (14, 17). Microarray analysis has been www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 30, 2017; DOI: 10.1158/1078-0432.CCR-17-1259 Simon et al. org/iric-soft/km) approaches according to the previously reported Translational Relevance pipeline (23). All variants present in 97 genes mutated in myeloid This study characterized the effect of RUNX1 allele dosage cancers or in acute leukemias were investigated (Supplementary on the gene expression profile and glucocorticoid sensitivity of Table S1). Genes and positions from Supplementary Table S5 primary RUNX1mut AML specimens. Our findings suggest a were also investigated by km approach described previously, using new role for RUNX1 in the glucocorticoid response and a 5% variant allele frequency (VAF) cutoff for missense and support the rationale to evaluate the addition of glucocorti- nonsense mutations as well as for indels confirmed by another coids in preclinical models of RUNX1mut AML. approach, of 10% for other indels. RUNX1 longest isoform (NM_001754/NP_001745.2) was used for representations. Primary AML cell culture and chemical screens RUNX1 – Freshly thawed primary AML specimens were used for chemical used to derive a mutation associated gene expression signature (17), however, a complete assessment of the mutational screens. Cryopreserved cells were thawed at 37 C in Iscove's fi and gene expression landscape of RUNX1mut AML is lacking. modi ed Dulbecco's medium (IMDM) containing 20% FBS and m Two types of mutations in RUNX1 have been described in AML: DNase I (100 g/mL). Cells were resuspended in IMDM supple- missense mutations found in the RUNT domain and nonsense or mented with 15% BIT (BSA, insulin, transferrin; StemCell Tech- frameshift mutations distributed throughout the entire gene. nologies), 100 ng/mL stem cell factor (Shenandoah 100-04), Some frameshift mutations located in the C-terminal region 50 ng/mL FLT3L (Shenandoah), 20 ng/mL IL3 (Shenandoah), À4 b produce elongated versions of the protein with intact DNA- 20 ng/mL G-CSF (Shenandoah), 10 mol/L -mercaptoethanol, m fl m binding activity that retain the ability to heterodimerize with gentamicin (50 g/mL), cipro oxacin (10 g/mL), SR1 CBFB, and that are believed to act as dominant negatives (10, 12, (500 nmol/L, Alichem), and UM729 (500 nmol/L, IRIC) and m 15, 18). Approximately 30% of RUNX1 mutations occur in 5,000 cells were plated per well of 384-well white plates in 50 L. combination (i.e., double heterozygosity) or are associated with Compounds were dissolved in DMSO and diluted in media a loss of heterozygosity, both of which lead to a complete loss of immediately before use. Compounds were added to plated cells fi wild-type RUNX1 in these leukemias (15). In line with this, it has by Biomek automatic pipettor at a nal DMSO concentration of been proposed that the greater the extent of RUNX1 inactivation 0.1%. Glucocorticoids were tested in the exploratory screen at m in hematopoietic cells, the higher the propensity to develop single doses of 2.5 mol/L as described previously (24). In the fi leukemia, suggesting a dependence on RUNX1 protein dosage con rmatory screen, compounds were added in serial dilutions for disease onset (19, 20). (ranging from 10,000 nmol/L to 4.5 nmol/L). Cells were grown in The unique genetic, biological, and clinical features of de novo culture in the presence of compounds for 6 days before deter- AMLs with mutated RUNX1 prompted its suggestion as a distinct mining cell viability using luminescent CellTiter Glo assay entity in the 2016 revision of the World Health Organization (Promega). Absolute IC50 values were calculated using Activity- (WHO) classification of myeloid neoplasms (21). The poor Base SARview Suite. For cases where compounds failed to inhibit outcome of patients suffering from RUNX1mut leukemias high- AML cell survival/proliferation, IC50 values were reported as the lights the need to better understand the genetics of this disease and highest concentration tested (10,000 nmol/L). Compounds that to develop more specific and efficient therapeutic strategies. In this showed more than 50% inhibition
Load more

Recommended publications
  • Variations in Microrna-25 Expression Influence the Severity of Diabetic
    BASIC RESEARCH www.jasn.org Variations in MicroRNA-25 Expression Influence the Severity of Diabetic Kidney Disease † † † Yunshuang Liu,* Hongzhi Li,* Jieting Liu,* Pengfei Han, Xuefeng Li, He Bai,* Chunlei Zhang,* Xuelian Sun,* Yanjie Teng,* Yufei Zhang,* Xiaohuan Yuan,* Yanhui Chu,* and Binghai Zhao* *Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Medical Research Center, Heilongjiang, People’s Republic of China; and †Clinical Laboratory of Hong Qi Hospital, Mudanjiang Medical University, Heilongjiang, People’s Republic of China ABSTRACT Diabetic nephropathy is characterized by persistent albuminuria, progressive decline in GFR, and second- ary hypertension. MicroRNAs are dysregulated in diabetic nephropathy, but identification of the specific microRNAs involved remains incomplete. Here, we show that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of microRNA-25 (miR-25) compared with those of their nondiabetic counterparts. Furthermore, treatment with high glucose decreased the expression of miR-25 in cultured kidney cells. In db/db mice, systemic administration of an miR-25 agomir repressed glomerular fibrosis and reduced high BP. Notably, knockdown of miR-25 in normal mice by systemic administration of an miR-25 antagomir resulted in increased proteinuria, extracellular matrix accumulation, podocyte foot process effacement, and hypertension with renin-angiotensin system activation. However, excessive miR-25 did not cause kidney dysfunction in wild-type mice. RNA sequencing showed the alteration of miR-25 target genes in antagomir-treated mice, including the Ras-related gene CDC42. In vitro,cotrans- fection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the CDC42 39 untranslated region.
    [Show full text]
  • (P -Value<0.05, Fold Change≥1.4), 4 Vs. 0 Gy Irradiation
    Table S1: Significant differentially expressed genes (P -Value<0.05, Fold Change≥1.4), 4 vs. 0 Gy irradiation Genbank Fold Change P -Value Gene Symbol Description Accession Q9F8M7_CARHY (Q9F8M7) DTDP-glucose 4,6-dehydratase (Fragment), partial (9%) 6.70 0.017399678 THC2699065 [THC2719287] 5.53 0.003379195 BC013657 BC013657 Homo sapiens cDNA clone IMAGE:4152983, partial cds. [BC013657] 5.10 0.024641735 THC2750781 Ciliary dynein heavy chain 5 (Axonemal beta dynein heavy chain 5) (HL1). 4.07 0.04353262 DNAH5 [Source:Uniprot/SWISSPROT;Acc:Q8TE73] [ENST00000382416] 3.81 0.002855909 NM_145263 SPATA18 Homo sapiens spermatogenesis associated 18 homolog (rat) (SPATA18), mRNA [NM_145263] AA418814 zw01a02.s1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE:767978 3', 3.69 0.03203913 AA418814 AA418814 mRNA sequence [AA418814] AL356953 leucine-rich repeat-containing G protein-coupled receptor 6 {Homo sapiens} (exp=0; 3.63 0.0277936 THC2705989 wgp=1; cg=0), partial (4%) [THC2752981] AA484677 ne64a07.s1 NCI_CGAP_Alv1 Homo sapiens cDNA clone IMAGE:909012, mRNA 3.63 0.027098073 AA484677 AA484677 sequence [AA484677] oe06h09.s1 NCI_CGAP_Ov2 Homo sapiens cDNA clone IMAGE:1385153, mRNA sequence 3.48 0.04468495 AA837799 AA837799 [AA837799] Homo sapiens hypothetical protein LOC340109, mRNA (cDNA clone IMAGE:5578073), partial 3.27 0.031178378 BC039509 LOC643401 cds. [BC039509] Homo sapiens Fas (TNF receptor superfamily, member 6) (FAS), transcript variant 1, mRNA 3.24 0.022156298 NM_000043 FAS [NM_000043] 3.20 0.021043295 A_32_P125056 BF803942 CM2-CI0135-021100-477-g08 CI0135 Homo sapiens cDNA, mRNA sequence 3.04 0.043389246 BF803942 BF803942 [BF803942] 3.03 0.002430239 NM_015920 RPS27L Homo sapiens ribosomal protein S27-like (RPS27L), mRNA [NM_015920] Homo sapiens tumor necrosis factor receptor superfamily, member 10c, decoy without an 2.98 0.021202829 NM_003841 TNFRSF10C intracellular domain (TNFRSF10C), mRNA [NM_003841] 2.97 0.03243901 AB002384 C6orf32 Homo sapiens mRNA for KIAA0386 gene, partial cds.
    [Show full text]
  • Genetic Testing for Acute Myeloid Leukemia AHS-M2062
    Corporate Medical Policy Genetic Testing for Acute Myeloid Leukemia AHS-M2062 File Name: genetic_testing_for_acute_myeloid_leukemia Origination: 1/1/2019 Last CAP Review: 8/2021 Next CAP Review: 8/2022 Last Review: 8/2021 Description of Procedure or Service Acute myeloid leukemia (AML) is characterized by large numbers of abnormal, immature myeloid cells in the bone marrow and peripheral blood resulting from genetic changes in hematopoietic precursor cells which disrupt normal hematopoietic growth and differentiation (Stock, 2020). Related Policies: Genetic Cancer Susceptibility Using Next Generation Sequencing AHS-M2066 Molecular Panel Testing of Cancers to Identify Targeted Therapy AHS-M2109 Serum Tumor Markers for Malignancies AHS-G2124 Minimal Residual Disease (MRD) AHS- M2175 ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for genetic testing for acute myeloid leukemia when it is determined to be medically necessary because the medical criteria and guidelines shown below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. When Genetic Testing for Acute Myeloid Leukemia is covered The use of genetic testing for acute myeloid leukemia is considered medically necessary for the following: A. Genetic testing for FLT3 internal tandem duplication and tyrosine kinase domain mutations (ITD and TKD), IDH1, IDH2, TET2, WT1, DNMT3A, ASXL1 and/or TP53 in adult and pediatric patients with suspected or confirmed AML of any type for prognostic and/or therapeutic purposes.
    [Show full text]
  • Application of Microrna Database Mining in Biomarker Discovery and Identification of Therapeutic Targets for Complex Disease
    Article Application of microRNA Database Mining in Biomarker Discovery and Identification of Therapeutic Targets for Complex Disease Jennifer L. Major, Rushita A. Bagchi * and Julie Pires da Silva * Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; [email protected] * Correspondence: [email protected] (R.A.B.); [email protected] (J.P.d.S.) Supplementary Tables Methods Protoc. 2021, 4, 5. https://doi.org/10.3390/mps4010005 www.mdpi.com/journal/mps Methods Protoc. 2021, 4, 5. https://doi.org/10.3390/mps4010005 2 of 25 Table 1. List of all hsa-miRs identified by Human microRNA Disease Database (HMDD; v3.2) analysis. hsa-miRs were identified using the term “genetics” and “circulating” as input in HMDD. Targets CAD hsa-miR-1 Targets IR injury hsa-miR-423 Targets Obesity hsa-miR-499 hsa-miR-146a Circulating Obesity Genetics CAD hsa-miR-423 hsa-miR-146a Circulating CAD hsa-miR-149 hsa-miR-499 Circulating IR Injury hsa-miR-146a Circulating Obesity hsa-miR-122 Genetics Stroke Circulating CAD hsa-miR-122 Circulating Stroke hsa-miR-122 Genetics Obesity Circulating Stroke hsa-miR-26b hsa-miR-17 hsa-miR-223 Targets CAD hsa-miR-340 hsa-miR-34a hsa-miR-92a hsa-miR-126 Circulating Obesity Targets IR injury hsa-miR-21 hsa-miR-423 hsa-miR-126 hsa-miR-143 Targets Obesity hsa-miR-21 hsa-miR-223 hsa-miR-34a hsa-miR-17 Targets CAD hsa-miR-223 hsa-miR-92a hsa-miR-126 Targets IR injury hsa-miR-155 hsa-miR-21 Circulating CAD hsa-miR-126 hsa-miR-145 hsa-miR-21 Targets Obesity hsa-mir-223 hsa-mir-499 hsa-mir-574 Targets IR injury hsa-mir-21 Circulating IR injury Targets Obesity hsa-mir-21 Targets CAD hsa-mir-22 hsa-mir-133a Targets IR injury hsa-mir-155 hsa-mir-21 Circulating Stroke hsa-mir-145 hsa-mir-146b Targets Obesity hsa-mir-21 hsa-mir-29b Methods Protoc.
    [Show full text]
  • Supplementary Materials and Tables a and B
    SUPPLEMENTARY MATERIAL 1 Table A. Main characteristics of the subset of 23 AML patients studied by high-density arrays (subset A) WBC BM blasts MYST3- MLL Age/Gender WHO / FAB subtype Karyotype FLT3-ITD NPM status (x109/L) (%) CREBBP status 1 51 / F M4 NA 21 78 + - G A 2 28 / M M4 t(8;16)(p11;p13) 8 92 + - G G 3 53 / F M4 t(8;16)(p11;p13) 27 96 + NA G NA 4 24 / M PML-RARα / M3 t(15;17) 5 90 - - G G 5 52 / M PML-RARα / M3 t(15;17) 1.5 75 - - G G 6 31 / F PML-RARα / M3 t(15;17) 3.2 89 - - G G 7 23 / M RUNX1-RUNX1T1 / M2 t(8;21) 38 34 - + ND G 8 52 / M RUNX1-RUNX1T1 / M2 t(8;21) 8 68 - - ND G 9 40 / M RUNX1-RUNX1T1 / M2 t(8;21) 5.1 54 - - ND G 10 63 / M CBFβ-MYH11 / M4 inv(16) 297 80 - - ND G 11 63 / M CBFβ-MYH11 / M4 inv(16) 7 74 - - ND G 12 59 / M CBFβ-MYH11 / M0 t(16;16) 108 94 - - ND G 13 41 / F MLLT3-MLL / M5 t(9;11) 51 90 - + G R 14 38 / F M5 46, XX 36 79 - + G G 15 76 / M M4 46 XY, der(10) 21 90 - - G NA 16 59 / M M4 NA 29 59 - - M G 17 26 / M M5 46, XY 295 92 - + G G 18 62 / F M5 NA 67 88 - + M A 19 47 / F M5 del(11q23) 17 78 - + M G 20 50 / F M5 46, XX 61 59 - + M G 21 28 / F M5 46, XX 132 90 - + G G 22 30 / F AML-MD / M5 46, XX 6 79 - + M G 23 64 / M AML-MD / M1 46, XY 17 83 - + M G WBC: white blood cell.
    [Show full text]
  • Maintenance of Mammary Epithelial Phenotype by Transcription Factor Runx1 Through Mitotic Gene Bookmarking Joshua Rose University of Vermont
    University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2019 Maintenance Of Mammary Epithelial Phenotype By Transcription Factor Runx1 Through Mitotic Gene Bookmarking Joshua Rose University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Biochemistry Commons, and the Genetics and Genomics Commons Recommended Citation Rose, Joshua, "Maintenance Of Mammary Epithelial Phenotype By Transcription Factor Runx1 Through Mitotic Gene Bookmarking" (2019). Graduate College Dissertations and Theses. 998. https://scholarworks.uvm.edu/graddis/998 This Thesis is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. MAINTENANCE OF MAMMARY EPITHELIAL PHENOTYPE BY TRANSCRIPTION FACTOR RUNX1 THROUGH MITOTIC GENE BOOKMARKING A Thesis Presented by Joshua Rose to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Master of Science Specializing in Cellular, Molecular, and Biomedical Sciences January, 2019 Defense Date: November 12, 2018 Thesis Examination Committee: Sayyed Kaleem Zaidi, Ph.D., Advisor Gary Stein, Ph.D., Advisor Seth Frietze, Ph.D., Chairperson Janet Stein, Ph.D. Jonathan Gordon, Ph.D. Cynthia J. Forehand, Ph.D. Dean of the Graduate College ABSTRACT Breast cancer arises from a series of acquired mutations that disrupt normal mammary epithelial homeostasis and create multi-potent cancer stem cells that can differentiate into clinically distinct breast cancer subtypes. Despite improved therapies and advances in early detection, breast cancer remains the leading diagnosed cancer in women.
    [Show full text]
  • Castration Delays Epigenetic Aging and Feminizes DNA
    RESEARCH ARTICLE Castration delays epigenetic aging and feminizes DNA methylation at androgen- regulated loci Victoria J Sugrue1, Joseph Alan Zoller2, Pritika Narayan3, Ake T Lu4, Oscar J Ortega-Recalde1, Matthew J Grant3, C Simon Bawden5, Skye R Rudiger5, Amin Haghani4, Donna M Bond1, Reuben R Hore6, Michael Garratt1, Karen E Sears7, Nan Wang8, Xiangdong William Yang8,9, Russell G Snell3, Timothy A Hore1†*, Steve Horvath4†* 1Department of Anatomy, University of Otago, Dunedin, New Zealand; 2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, United States; 3Applied Translational Genetics Group, School of Biological Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand; 4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; 5Livestock and Farming Systems, South Australian Research and Development Institute, Roseworthy, Australia; 6Blackstone Hill Station, Becks, RD2, Omakau, New Zealand; 7Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, United States; 8Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, United States; 9Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, United States *For correspondence: Abstract In mammals, females generally live longer than males. Nevertheless, the mechanisms [email protected] (TAH); underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful [email protected] (SH) biological biomarkers capable of precisely estimating chronological age and identifying novel †These authors contributed factors influencing the aging rate using only DNA methylation data. In this study, we developed the equally to this work first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months.
    [Show full text]
  • Engineered Type 1 Regulatory T Cells Designed for Clinical Use Kill Primary
    ARTICLE Acute Myeloid Leukemia Engineered type 1 regulatory T cells designed Ferrata Storti Foundation for clinical use kill primary pediatric acute myeloid leukemia cells Brandon Cieniewicz,1* Molly Javier Uyeda,1,2* Ping (Pauline) Chen,1 Ece Canan Sayitoglu,1 Jeffrey Mao-Hwa Liu,1 Grazia Andolfi,3 Katharine Greenthal,1 Alice Bertaina,1,4 Silvia Gregori,3 Rosa Bacchetta,1,4 Norman James Lacayo,1 Alma-Martina Cepika1,4# and Maria Grazia Roncarolo1,2,4# Haematologica 2021 Volume 106(10):2588-2597 1Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 2Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy and 4Center for Definitive and Curative Medicine, Stanford School of Medicine, Stanford, CA, USA *BC and MJU contributed equally as co-first authors #AMC and MGR contributed equally as co-senior authors ABSTRACT ype 1 regulatory (Tr1) T cells induced by enforced expression of interleukin-10 (LV-10) are being developed as a novel treatment for Tchemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft-versus-host disease while mediating graft-versus-leukemia effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature.
    [Show full text]
  • The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib Plus Fulvestrant in the PALOMA-3 Trial
    Published OnlineFirst September 11, 2018; DOI: 10.1158/2159-8290.CD-18-0264 RESEARCH ARTICLE The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial Ben O’Leary1,2, Rosalind J. Cutts1, Yuan Liu3, Sarah Hrebien1, Xin Huang3, Kerry Fenwick4, Fabrice André5, Sibylle Loibl6, Sherene Loi7, Isaac Garcia-Murillas1, Massimo Cristofanilli8, Cynthia Huang Bartlett3, and Nicholas C. Turner1,2 Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst September 11, 2018; DOI: 10.1158/2159-8290.CD-18-0264 ABSTRACT CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor–positive breast cancer. Mechanisms of CDK4/6 inhibitor resist- ance have been described preclinically, with limited evidence from clinical samples. We conducted paired baseline and end-of-treatment circulating tumor DNA sequencing from 195 patients in the PALOMA-3 randomized phase III trial of palbociclib plus fulvestrant versus placebo plus fulvestrant. We show that clonal evolution occurs frequently during treatment, refl ecting substantial subclonal complexity in breast cancer that has progressed after prior endocrine therapy. RB1 mutations emerged only in the palbociclib plus fulvestrant arm and in a minority of patients (6/127, 4.7%, P = 0.041). New driver mutations emerged in PIK3CA (P = 0.00069) and ESR1 after treatment in both arms, in particular ESR1 Y537S (P = 0.0037). Evolution of driver gene mutations was uncommon in patients progressing early on palbociclib plus fulvestrant but common in patients progressing later on treatment. These fi nd- ings inform future treatment strategies to address resistance to palbociclib plus fulvestrant.
    [Show full text]
  • Interplay Between Cofactors and Transcription Factors in Hematopoiesis and Hematological Malignancies
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies Zi Wang 1,2, Pan Wang2, Yanan Li2, Hongling Peng1, Yu Zhu2, Narla Mohandas3 and Jing Liu2 Hematopoiesis requires finely tuned regulation of gene expression at each stage of development. The regulation of gene transcription involves not only individual transcription factors (TFs) but also transcription complexes (TCs) composed of transcription factor(s) and multisubunit cofactors. In their normal compositions, TCs orchestrate lineage-specific patterns of gene expression and ensure the production of the correct proportions of individual cell lineages during hematopoiesis. The integration of posttranslational and conformational modifications in the chromatin landscape, nucleosomes, histones and interacting components via the cofactor–TF interplay is critical to optimal TF activity. Mutations or translocations of cofactor genes are expected to alter cofactor–TF interactions, which may be causative for the pathogenesis of various hematologic disorders. Blocking TF oncogenic activity in hematologic disorders through targeting cofactors in aberrant complexes has been an exciting therapeutic strategy. In this review, we summarize the current knowledge regarding the models and functions of cofactor–TF interplay in physiological hematopoiesis and highlight their implications in the etiology of hematological malignancies. This review presents a deep insight into the physiological and pathological implications of transcription machinery in the blood system. Signal Transduction and Targeted Therapy (2021) ;6:24 https://doi.org/10.1038/s41392-020-00422-1 1234567890();,: INTRODUCTION by their ATPase subunits into four major families, including the Hematopoiesisisacomplexhierarchicaldifferentiationprocessthat SWI/SNF, ISWI, Mi-2/NuRD, and INO80/SWR1 families.
    [Show full text]
  • (NGS) for Primary Endocrine Resistance in Breast Cancer Patients
    Int J Clin Exp Pathol 2018;11(11):5450-5458 www.ijcep.com /ISSN:1936-2625/IJCEP0084102 Original Article Impact of next-generation sequencing (NGS) for primary endocrine resistance in breast cancer patients Ruoyang Li1*, Tiantian Tang1*, Tianli Hui1, Zhenchuan Song1, Fugen Li2, Jingyu Li2, Jiajia Xu2 1Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China; 2Institute of Precision Medicine, 3D Medicines Inc., Shanghai, China. *Equal contributors. Received August 15, 2018; Accepted September 22, 2018; Epub November 1, 2018; Published November 15, 2018 Abstract: Multiple mechanisms have been detected to account for the acquired resistance to endocrine therapies in breast cancer. In this study we retrospectively studied the mechanism of primary endocrine resistance in estrogen receptor positive (ER+) breast cancer patients by next-generation sequencing (NGS). Tumor specimens and matched blood samples were obtained from 24 ER+ breast cancer patients. Fifteen of them displayed endocrine resistance, including recurrence and/or metastases within 24 months from the beginning of endocrine therapy, and 9 pa- tients remained sensitive to endocrine therapy for more than 5 years. Genomic DNA of tumor tissue was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks. Genomic DNA of normal tissue was extracted from peripheral blood mononuclear cells (PBMC). Sequencing libraries for each sample were prepared, followed by target capturing for 372 genes that are frequently rearranged in cancers. Massive parallel
    [Show full text]
  • Investigating Caveolin-Dependent Glucocorticoid Action in Inflammation
    Investigating caveolin-dependent glucocorticoid action in inflammation A thesis submitted to the University of Manchester for the degree of M.Phil in the Faculty of Medicine and Human Sciences 2013 Anna Louise Mary Mannion-Jones School of Medicine 1 Contents I. TABLES AND FIGURES .................................................................................................. 7 II. Abstract .................................................................................................................... 10 III. Declaration ............................................................................................................ 10 IV. Notice of Copyright................................................................................................ 11 1 Introduction .............................................................................................................. 18 1.1 Inflammation ..................................................................................................... 18 1.1.1 The cellular inflammatory response ........................................................... 18 1.1.2 Innate vs. adaptive immunity ..................................................................... 19 1.1.3 Chronic inflammation ................................................................................. 20 1.1.4 Autoimmune disease.................................................................................. 20 1.1.5 Anti-inflammatory actions of glucocorticoids ............................................. 22 1.1.6 The
    [Show full text]