This work examines the involvement of chromatin looping in the transcriptional regulation of two epialleles of the maize (Zea mays) b1 gene, B-I and B'. These two epialleles are tissue-specifically regulated and are involved in paramutation. B-I and B' are expressed at high and low levels, respectively. A hepta-repeat ;100 kb upstream of the transcription start site (TSS) is required for both paramutation and high b1 expression. Using chromosome conformation capture, we show that the heptarepeat physically interacts with the TSS region in a tissue-and expression level-specific manner. Multiple repeats are required to stabilize this interaction. High b1 expression is mediated by a multiloop structure; besides the hepta-repeat, other sequence regions physically interact with the TSS as well, and these interactions are epiallele-and expression levelspecific. Formaldehyde-assisted isolation of regulatory elements uncovered multiple interacting regions as potentially regulatory.
SUMMARYParamutation is the transfer of epigenetic information between alleles that leads to a heritable change in expression of one of these alleles. Paramutation at the tissue-specifically expressed maize (Zea mays) b1 locus involves the low-expressing B¢ and high-expressing B-I allele. Combined in the same nucleus, B¢ heritably changes B-I into B¢. A hepta-repeat located 100-kb upstream of the b1 coding region is required for paramutation and for high b1 expression. The role of epigenetic modifications in paramutation is currently not well understood. In this study, we show that the B¢ hepta-repeat is DNA-hypermethylated in all tissues analyzed. Importantly, combining B¢ and B-I in one nucleus results in de novo methylation of the B-I repeats early in plant development. These findings indicate a role for hepta-repeat DNA methylation in the establishment and maintenance of the silenced B¢ state. In contrast, nucleosome occupancy, H3 acetylation, and H3K9 and H3K27 methylation are mainly involved in tissue-specific regulation of the hepta-repeat. Nucleosome depletion and H3 acetylation are tissue-specifically regulated at the B-I hepta-repeat and associated with enhancement of b1 expression. H3K9 and H3K27 methylation are tissue-specifically localized at the B¢ hepta-repeat and reinforce the silenced B¢ chromatin state. The B¢ coding region is H3K27 dimethylated in all tissues analyzed, indicating a role in the maintenance of the silenced B¢ state. Taken together, these findings provide insight into the mechanisms underlying paramutation and tissue-specific regulation of b1 at the level of chromatin structure.
Background: Acute myeloid leukemia (AML) is driven by aberrant leukemic stem cells (LSCs) that initiate and sustain malignancy. To circumvent resistance to therapy, combination therapies with additive mechanisms of action are needed. CD70, a tumor necrosis factor receptor ligand, and its receptor CD27 are expressed on LSCs and AML blasts, but not on hematopoietic stem cells. Cusatuzumab, a high-affinity humanized monoclonal anti-CD70 antibody, kills CD70-expressing cells by Fc domain-mediated effector functions and is a potent inhibitor of CD70-CD27 signaling. Here we report initial results of a study of cusatuzumab in combination with the current standard of care therapy, venetoclax plus azacitidine (CVA), in patients with untreated AML (de novo or secondary) ineligible for intensive chemotherapy due to age ≥75 years or medical comorbidities. Methods: The primary objective of this open label, multicenter, phase 1b study was to assess safety and tolerability of CVA. Key secondary objectives included response rate per ELN 2017 criteria and time to response. Patients received cusatuzumab 10 or 20 mg/kg IV on Day 3 and Day 17, a 3-day ramp-up of venetoclax (100, 200, and 400 mg PO) followed by 400 mg daily dosing, and azacitidine 75 mg/m 2 SC or IV on Days 1-7 of each 28-day cycle. Results: Based on data through Jul 9, 2021, 44 patients enrolled with median age 75 years (range 32-89), 36.4% had secondary AML, 40.9% had an ECOG performance status of 2, and ELN risk was favorable, intermediate and adverse in 18.2%, 20.5% and 61.4%, respectively. All patients received 20 mg/kg cusatuzumab except for 3 patients who received a starting dose of 10 mg/kg with the option to escalate to 20 mg/kg. Of these 3 patients, 1 escalated to 20 mg/kg. At a median follow-up of 29.1 weeks, the median number of treatment cycles was 4.0 (range 1.0-11.0). Grade 3 or above TEAEs were reported in 97.7% of patients; the most common (reported in ≥10%) were neutropenia (68.2%), thrombocytopenia (65.9%), febrile neutropenia (36.4%), anemia (34.1%), leukopenia (29.5%), sepsis (27.3%), and lymphopenia (15.9%). Treatment-emergent serious adverse events (SAEs) were reported in 75% of patients; the most common (reported in at least ≥5%) were febrile neutropenia (27.3%), sepsis (22.7%), COVID-19 (6.8%), and thrombocytopenia (6.8%). Treatment-emergent SAEs of grade ≥3 were reported in 72.7% of the patients. Infusion-related reactions (IRRs) were reported for 11.4% of patients with 2.3% at grade ≥3. Six (13.6%) patients discontinued treatment due to AEs, and 5 (11.4%) TEAEs resulted in death. The mortality rate within 30 days from start of treatment was 4.5%. Table 1 summarizes best response to study treatment. In the intent-to-treat analysis set (n=44) complete remission (CR) rate was 45.5%, while CR + CR with partial hematologic recovery (CRh) + CR with incomplete hematologic recovery (CRi) was 77.3%; MLFS was observed in 11.4% of patients. Of 34 responders (defined as CR, CRi or CRh), 47% were MRD negative by flow cytometry at or after achievement of response. Median time to first response for patients who achieved CR, CRh or CRi was 4.21 (3.0-25.0) weeks. Best response rates in the post-hoc response evaluable analysis set (n=42) that excluded two patients who died before the first disease evaluation were: CR in 47.6%, CR + CRh + CRi in 81.0% and MLFS in 11.9% of patients (Table 1). The majority (97.1%) of responders experienced at least one cycle delay in administration of CVA post response. Conclusions: Cusatuzumab administered in combination with venetoclax and azacitidine to elderly patients with untreated AML was generally well tolerated and demonstrated a safety profile consistent with that previously reported with venetoclax-azacitidine, with the addition of generally manageable IRRs. Response rates support an additive effect of cusatuzumab to the standard of care with potential for improved clinical outcomes. However, further clinical trials are needed for validation of these initial results. HK and GB contributed equally to this publication. Figure 1 Figure 1. Disclosures Roboz: AstraZeneca: Consultancy; Janssen: Research Funding; Bristol Myers Squibb: Consultancy; Jasper Therapeutics: Consultancy; Agios: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Blueprint Medicines: Consultancy; Janssen: Consultancy; Helsinn: Consultancy; Daiichi Sankyo: Consultancy; Glaxo SmithKline: Consultancy; Celgene: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Astex: Consultancy; Bayer: Consultancy; Astellas: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy. Aribi: Seagen: Consultancy. Brandwein: Astellas: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Taiho: Honoraria; BMS/Celgene: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; University of Alberta: Current Employment. 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Fiedler: Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; ARIAD/Incyte: Consultancy; Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding; Servier: Consultancy, Other: support for meeting attendance; Daiichi Sankyo: Consultancy, Other: support for meeting attendance; Stemline: Consultancy. Gandini: argenx: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Geddes: University of Calgary: Current Employment; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Paladin: Consultancy; Janssen: Research Funding; Geron: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hou: University of Pittsburgh Medical Center Hillman Cancer Centers: Current Employment; AbbVie: Honoraria; AstraZeneca: Honoraria; Karyopharm: Honoraria; Chinese American Hematology Oncology Network: Membership on an entity's Board of Directors or advisory committees. Howes: Janssen R&D, part of Johnson & Johnson: Current Employment; Johnson & Johnson: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hultberg: argenx: Current Employment, Patents & Royalties. Huselton: University of Rochester: Current Employment. Jacobs: Argenx BV: Current Employment, Current equity holder in publicly-traded company; University of Antwerp: Ended employment in the past 24 months. Kane: Janssen R&D, part of Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Lech-Marańda: Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Louwers: argenx: Current Employment, Patents & Royalties: Patents (no royalties). Nottage: Janssen R&D, part of Johnson & Johnson: Current Employment; Johnson & Johnson: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Platzbecker: Novartis: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; Takeda: Honoraria. Rampal: Pharmaessentia: Consultancy; BMS/Celgene: Consultancy; Abbvie: Consultancy; Sierra Oncology: Consultancy; Incyte: Consultancy, Research Funding; Blueprint: Consultancy; Disc Medicine: Consultancy; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Kartos: Consultancy; Stemline: Consultancy, Research Funding; CTI: Consultancy; Novartis: Consultancy; Memorial Sloan Kettering: Current Employment. Salman: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shah: Janssen R&D, part of Johnson & Johnson: Current Employment. Stuart: Clinical Drug Development Consultants LLC: Current Employment; Argenx: Consultancy; Cleave Therapeutics: Consultancy; Triphase Accelerator Corp: Consultancy; IgM Biosciences: Consultancy; Revolution Medicines: Consultancy; Jiya Corp: Consultancy; Geron Corp: Current holder of individual stocks in a privately-held company. Subklewe: Janssen: Consultancy; Pfizer: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Klinikum der Universität München: Current Employment; MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Research Funding; Seattle Genetics: Consultancy, Research Funding; Miltenyi: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. Sumbul: argenx: Current Employment. 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The sections in this article areIntroductionParamutation across KingdomsParamutation ModelsCommon Features of Paramutation PhenomenaTrans‐Acting Mutations Affecting ParamutationThe Possible Roles and Implications of ParamutationConcluding Remarks and Future DirectionsAcknowledgments
Paramutation is the heritable transfer of epigenetic information from one allele of a gene to another allele of the same gene. In general, the consequence of this trans-communication is a change in gene expression. Paramutation has been observed in plants, fungi and mammals, but is most extensively studied in maize thanks to the long-standing history of maize genetics. For decades, paramutation has been a mystery, but recent progress has shed light on the mechanisms underlying this phenomenon. The identification of MOP1 as an RNA-dependent RNA polymerase shows that RNA plays a crucial role in the trans-inactivation process. RNA however appears not the only player in the paramutation process. In this chapter, potential mechanisms will be discussed in light of characteristics that the various paramutation phenomena have in common.
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