Modelling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs.
BET inhibitor
MECOM
enhancer hijacking
iPSC
myeloid neoplasm
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
26 Aug 2024
26 Aug 2024
Historique:
received:
03
04
2024
accepted:
11
08
2024
medline:
27
8
2024
pubmed:
27
8
2024
entrez:
26
8
2024
Statut:
aheadofprint
Résumé
Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP21K08414
Organisme : Research Center Network for Realization of Regenerative Medicine (Japan Agency for Medical Research and Development)
ID : JP20bm0104001
Organisme : Research Center Network for Realization of Regenerative Medicine (Japan Agency for Medical Research and Development)
ID : JP20bm0804004
Organisme : Acceleration Program of R&D and implementation for Regenerative Medicine and Cell and Gene Therapy (Japan Agency for Medical Research and Development)
ID : JP23bm1323001
Organisme : Acceleration Program of R&D and implementation for Regenerative Medicine and Cell and Gene Therapy (Japan Agency for Medical Research and Development)
ID : JP23bm1423011
Organisme : Project for Cancer Research and Therapeutic Evolution (Japan Agency for Medical Research and Development)
ID : JP19cm0106235
Organisme : Mochida Memorial Foundation for Medical and Pharmaceutical Research
Organisme : Yasuda Memorial Medical Foundation
Organisme : Kobayashi Foundation for Cancer Research
Organisme : Daiichi Sankyo Foundation of Life Science
Organisme : Fondation Leducq
ID : 18CVD05
Organisme : iPS Cell Research Fund
Informations de copyright
© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Claringbould A, Zaugg JB. Enhancers in disease: molecular basis and emerging treatment strategies. Trends Mol Med. 2021;27(11):1060–1073.
Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature. 2014;511(7510):428–434.
Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick S, et al. Translocation of the c‐myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A. 1982;79(24):7837–7841.
Cleary ML, Sklar J. Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint‐cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci U S A. 1985;82(21):7439–7443.
Gröschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BAM, Erpelinck C, et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell. 2014;157(2):369–381.
Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD, et al. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell. 2014;25(4):415–427.
Lugthart S, Gröschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen‐Bhola SL, et al. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol. 2010;28(24):3890–3898.
Rogers HJ, Vardiman JW, Anastasi J, Raca G, Savage NM, Cherry AM, et al. Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a bone marrow pathology group study. Haematologica. 2014;99(5):821–829.
Sasaki K, Montalban‐Bravo G, Kanagal‐Shamanna R, Jabbour E, Ravandi F, Kadia T, et al. Natural history of newly diagnosed myelodysplastic syndrome with isolated inv(3)/t(3;3). Am J Hematol. 2020;95(12):E326–e9.
Hu Z, Hu S, Ji C, Tang Z, Thakral B, Loghavi S, et al. 3q26/EVI1 rearrangement in myelodysplastic/myeloproliferative neoplasms: an early event associated with a poor prognosis. Leuk Res. 2018;65:25–28.
Ottema S, Mulet‐Lazaro R, Beverloo HB, Erpelinck C, van Herk S, van der Helm R, et al. Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia. Blood. 2020;136(2):224–234.
Ottema S, Mulet‐Lazaro R, Erpelinck‐Verschueren C, van Herk S, Havermans M, Arricibita Varea A, et al. The leukemic oncogene EVI1 hijacks a MYC super‐enhancer by CTCF‐facilitated loops. Nat Commun. 2021;12(1):5679.
Tang G, Hu S, Wang SA, Xie W, Lin P, Xu J, et al. T(3;8)(q26.2;q24) often leads to MECOM/MYC rearrangement and is commonly associated with therapy‐related myeloid neoplasms and/or disease progression. J Mol Diagn. 2019;21(2):343–351.
Xu X, Su M, Levy NB, Mohtashamian A, Monaghan S, Kaur P, et al. Myeloid neoplasm with t(3;8)(q26;q24): report of six cases and review of the literature. Leuk Lymphoma. 2014;55(11):2532–2537.
Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703–1719.
Montefiori LE, Bendig S, Gu Z, Chen X, Pölönen P, Ma X, et al. Enhancer hijacking drives oncogenic BCL11B expression in lineage‐ambiguous stem cell leukemia. Cancer Discov. 2021;11(11):2846–2867.
Kubota S, Tokunaga K, Umezu T, Yokomizo‐Nakano T, Sun Y, Oshima M, et al. Lineage‐specific RUNX2 super‐enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm. Nat Commun. 2019;10(1):1653.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–872.
Kotini AG, Chang CJ, Boussaad I, Delrow JJ, Dolezal EK, Nagulapally AB, et al. Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nat Biotechnol. 2015;33(6):646–655.
Garçon L, Ge J, Manjunath SH, Mills JA, Apicella M, Parikh S, et al. Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from diamond Blackfan anemia patients. Blood. 2013;122(6):912–921.
Imamura K, Izumi Y, Watanabe A, Tsukita K, Woltjen K, Yamamoto T, et al. The Src/c‐Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci Transl Med. 2017;9(391):eaaf3962.
Chao MP, Gentles AJ, Chatterjee S, Lan F, Reinisch A, Corces MR, et al. Human AML‐iPSCs reacquire leukemic properties after differentiation and model clonal variation of disease. Cell Stem Cell. 2017;20(3):329–44.e7.
Okita K, Yamakawa T, Matsumura Y, Sato Y, Amano N, Watanabe A, et al. An efficient nonviral method to generate integration‐free human‐induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells. 2013;31(3):458–466.
Voit RA, Tao L, Yu F, Cato LD, Cohen B, Fleming TJ, et al. A genetic disorder reveals a hematopoietic stem cell regulatory network co‐opted in leukemia. Nat Immunol. 2023;24(1):69–83.
Bahr C, von Paleske L, Uslu VV, Remeseiro S, Takayama N, Ng SW, et al. A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies. Nature. 2018;553(7689):515–520.
Stathis A, Bertoni F. BET proteins as targets for anticancer treatment. Cancer Discov. 2018;8(1):24–36.
Yoshino S, Yokoyama T, Sunami Y, Takahara T, Nakamura A, Yamazaki Y, et al. Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9. Blood. 2021;137(1):75–88.
Morimoto S, Takahashi S, Fukushima K, Saya H, Suzuki N, Aoki M, et al. Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis ‐ protocol for a randomized, double‐blind, placebo‐controlled, single‐center, and open‐label continuation phase I/IIa clinical trial (ROPALS trial). Regen Ther. 2019;11:143–166.
Imamura K, Izumi Y, Banno H, Uozumi R, Morita S, Egawa N, et al. Induced pluripotent stem cell‐based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients. BMJ Open. 2019;9(12):e033131.
Kotini AG, Chang CJ, Chow A, Yuan H, Ho TC, Wang T, et al. Stage‐specific human induced pluripotent stem cells map the progression of myeloid transformation to transplantable leukemia. Cell Stem Cell. 2017;20(3):315–28.e7.
Ye Z, Liu CF, Lanikova L, Dowey SN, He C, Huang X, et al. Differential sensitivity to JAK inhibitory drugs by isogenic human erythroblasts and hematopoietic progenitors generated from patient‐specific induced pluripotent stem cells. Stem Cells. 2014;32(1):269–278.