nach oben

Erschienen in:

21.06.2020 | Original Article

UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells

verfasst von: Tiwaporn Nualkaew, Pinyaphat Khamphikham, Phitchapa Pongpaksupasin, Woratree Kaewsakulthong, Duantida Songdej, Kittiphong Paiboonsukwong, Orapan Sripichai, James Douglas Engel, Suradej Hongeng, Suthat Fucharoen, Natee Jearawiriyapaisarn

Erschienen in: Annals of Hematology | Ausgabe 9/2020

Einloggen, um Zugang zu erhalten

Abstract

Increased expression of fetal hemoglobin (HbF) improves the clinical severity of β-thalassemia patients. EHMT1/2 histone methyltransferases are epigenetic modifying enzymes that are responsible for catalyzing addition of the repressive histone mark H3K9me2 at silenced genes, including the γ-globin genes. UNC0638, a chemical inhibitor of EHMT1/2, has been shown to induce HbF expression in human erythroid progenitor cell cultures. Here, we report the HbF-inducing activity of UNC0638 in erythroid progenitor cells from β-thalassemia/HbE patients. UNC0638 treatment led to significant increases in γ-globin mRNA, HbF expression, and HbF-containing cells in the absence of significant cytotoxicity. Moreover, UNC0638 showed additive effects on HbF induction in combination with the immunomodulatory drug pomalidomide and the DNMT1 inhibitor decitabine. These studies provide a scientific proof of concept that a small molecule targeting EHMT1/2 epigenetic enzymes, used alone or in combination with pomalidomide or decitabine, is a potential therapeutic approach for HbF induction. Further development of structural analogs of UNC0638 with similar biological effects but improved pharmacokinetic properties may lead to promising therapies and possible clinical application for the treatment of β-thalassemia.

Nur mit Berechtigung zugänglich

Weatherall DJ (2010) The inherited diseases of hemoglobin are an emerging global health burden. Blood 115(22):4331–4336. https://doi.org/10.1182/blood-2010-01-251348CrossRefPubMedPubMedCentral

Galanello R, Origa R (2010) Beta-thalassemia. Orphanet J Rare Dis 5:11. https://doi.org/10.1186/1750-1172-5-11CrossRefPubMedPubMedCentral

Rund D, Rachmilewitz E (2005) Beta-thalassemia. N Engl J Med 353(11):1135–1146. https://doi.org/10.1056/NEJMra050436CrossRefPubMed

Olivieri NF, Pakbaz Z, Vichinsky E (2011) Hb E/beta-thalassaemia: a common & clinically diverse disorder. Indian J Med Res 134:522–531PubMedPubMedCentral

Fucharoen S, Weatherall DJ (2012) The hemoglobin E thalassemias. Cold Spring Harb Perspect Med 2(8). https://doi.org/10.1101/cshperspect.a011734

Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarre C, Beuzard Y, Chretien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M (2018) Gene therapy in patients with transfusion-dependent beta-Thalassemia. N Engl J Med 378(16):1479–1493. https://doi.org/10.1056/NEJMoa1705342CrossRefPubMed

Winichagoon P, Fucharoen S, Chen P, Wasi P (2000) Genetic factors affecting clinical severity in beta-thalassemia syndromes. J Pediatr Hematol Oncol 22(6):573–580. https://doi.org/10.1097/00043426-200011000-00026CrossRefPubMed

Sripichai O, Munkongdee T, Kumkhaek C, Svasti S, Winichagoon P, Fucharoen S (2008) Coinheritance of the different copy numbers of alpha-globin gene modifies severity of beta-thalassemia/Hb E disease. Ann Hematol 87(5):375–379. https://doi.org/10.1007/s00277-007-0407-2CrossRefPubMed

Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O, Kumasaka N, Takahashi A, Svasti S, Munkongdee T, Mahasirimongkol S, Peerapittayamongkol C, Viprakasit V, Kamatani N, Winichagoon P, Kubo M, Nakamura Y, Fucharoen S (2010) A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet 127(3):303–314. https://doi.org/10.1007/s00439-009-0770-2CrossRefPubMed

10.

Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR (1995) Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med 332(20):1317–1322. https://doi.org/10.1056/NEJM199505183322001CrossRefPubMed

11.

Fucharoen S, Siritanaratkul N, Winichagoon P, Chowthaworn J, Siriboon W, Muangsup W, Chaicharoen S, Poolsup N, Chindavijak B, Pootrakul P, Piankijagum A, Schechter AN, Rodgers GP (1996) Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease. Blood 87(3):887–892CrossRef

12.

Loukopoulos D, Voskaridou E, Stamoulakatou A, Papassotiriou Y, Kalotychou V, Loutradi A, Cozma G, Tsiarta H, Pavlides N (1998) Hydroxyurea therapy in thalassemia. Ann N Y Acad Sci 850:120–128. https://doi.org/10.1111/j.1749-6632.1998.tb10469.xCrossRefPubMed

13.

Fathallah H, Sutton M, Atweh GF (2005) Pharmacological induction of fetal hemoglobin: why haven't we been more successful in thalassemia? Ann N Y Acad Sci 1054:228–237. https://doi.org/10.1196/annals.1345.029CrossRefPubMed

14.

Musallam KM, Taher AT, Cappellini MD, Sankaran VG (2013) Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia. Blood 121(12):2199–2212; quiz 2372. https://doi.org/10.1182/blood-2012-10-408021CrossRefPubMed

15.

Platt OS (2008) Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med 358(13):1362–1369. https://doi.org/10.1056/NEJMct0708272CrossRefPubMed

16.

Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP, Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell D (2018) A phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med 379(3):226–235. https://doi.org/10.1056/NEJMoa1715971CrossRefPubMed

17.

Cui S, Kolodziej KE, Obara N, Amaral-Psarris A, Demmers J, Shi L, Engel JD, Grosveld F, Strouboulis J, Tanabe O (2011) Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic beta-type globin promoters in differentiated adult erythroid cells. Mol Cell Biol 31(16):3298–3311. https://doi.org/10.1128/MCB.05310-11CrossRefPubMedPubMedCentral

18.

Xu J, Bauer DE, Kerenyi MA, Vo TD, Hou S, Hsu YJ, Yao H, Trowbridge JJ, Mandel G, Orkin SH (2013) Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci U S A 110(16):6518–6523. https://doi.org/10.1073/pnas.1303976110CrossRefPubMedPubMedCentral

19.

Lavelle D, Engel JD, Saunthararajah Y (2018) Fetal hemoglobin induction by epigenetic drugs. Semin Hematol 55(2):60–67. https://doi.org/10.1053/j.seminhematol.2018.04.008CrossRefPubMedPubMedCentral

20.

Olivieri NF, Saunthararajah Y, Thayalasuthan V, Kwiatkowski J, Ware RE, Kuypers FA, Kim HY, Trachtenberg FL, Vichinsky EP, Thalassemia Clinical Research N (2011) A pilot study of subcutaneous decitabine in beta-thalassemia intermedia. Blood 118(10):2708–2711. https://doi.org/10.1182/blood-2011-03-341909CrossRefPubMedPubMedCentral

21.

Fucharoen S, Inati A, Siritanaratku N, Thein SL, Wargin WC, Koussa S, Taher A, Chaneim N, Boosalis M, Berenson R, Perrine SP (2013) A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in beta-thalassaemia intermedia and HbE/beta-thalassaemia. Br J Haematol 161(4):587–593. https://doi.org/10.1111/bjh.12304CrossRefPubMedPubMedCentral

22.

Shi L, Cui S, Engel JD, Tanabe O (2013) Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med 19(3):291–294. https://doi.org/10.1038/nm.3101CrossRefPubMedPubMedCentral

23.

Cui S, Lim KC, Shi L, Lee M, Jearawiriyapaisarn N, Myers G, Campbell A, Harro D, Iwase S, Trievel RC, Rivers A, DeSimone J, Lavelle D, Saunthararajah Y, Engel JD (2015) The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice. Blood 126(3):386–396. https://doi.org/10.1182/blood-2015-02-626259CrossRefPubMedPubMedCentral

24.

Krivega I, Byrnes C, de Vasconcellos JF, Lee YT, Kaushal M, Dean A, Miller JL (2015) Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/gamma-globin looping. Blood 126(5):665–672. https://doi.org/10.1182/blood-2015-02-629972CrossRefPubMedPubMedCentral

25.

Renneville A, Van Galen P, Canver MC, McConkey M, Krill-Burger JM, Dorfman DM, Holson EB, Bernstein BE, Orkin SH, Bauer DE, Ebert BL (2015) EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood 126(16):1930–1939. https://doi.org/10.1182/blood-2015-06-649087CrossRefPubMedPubMedCentral

26.

Moutouh-de Parseval LA, Verhelle D, Glezer E, Jensen-Pergakes K, Ferguson GD, Corral LG, Morris CL, Muller G, Brady H, Chan K (2008) Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest 118(1):248–258. https://doi.org/10.1172/JCI32322CrossRefPubMed

27.

Dulmovits BM, Appiah-Kubi AO, Papoin J, Hale J, He M, Al-Abed Y, Didier S, Gould M, Husain-Krautter S, Singh SA, Chan KW, Vlachos A, Allen SL, Taylor N, Marambaud P, An X, Gallagher PG, Mohandas N, Lipton JM, Liu JM, Blanc L (2016) Pomalidomide reverses gamma-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors. Blood 127(11):1481–1492. https://doi.org/10.1182/blood-2015-09-667923CrossRefPubMedPubMedCentral

28.

Khamphikham P, Nualkaew T, Pongpaksupasin P, Kaewsakulthong W, Songdej D, Paiboonsukwong K, Engel JD, Hongeng S, Fucharoen S, Sripichai O, Jearawiriyapaisarn N (2020) High-level induction of fetal haemoglobin by pomalidomide in beta-thalassaemia/HbE erythroid progenitor cells. Br J Haematol. https://doi.org/10.1111/bjh.16670

29.

Sripichai O, Kiefer CM, Bhanu NV, Tanno T, Noh SJ, Goh SH, Russell JE, Rognerud CL, Ou CN, Oneal PA, Meier ER, Gantt NM, Byrnes C, Lee YT, Dean A, Miller JL (2009) Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming. Blood 114(11):2299–2306. https://doi.org/10.1182/blood-2009-05-219386CrossRefPubMedPubMedCentral

30.

Shinkai Y, Tachibana M (2011) H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev 25(8):781–788. https://doi.org/10.1101/gad.2027411CrossRefPubMedPubMedCentral

31.

Chen X, Skutt-Kakaria K, Davison J, Ou YL, Choi E, Malik P, Loeb K, Wood B, Georges G, Torok-Storb B, Paddison PJ (2012) G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev 26(22):2499–2511. https://doi.org/10.1101/gad.200329.112CrossRefPubMedPubMedCentral

32.

Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A (2008) Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A 105(5):1620–1625. https://doi.org/10.1073/pnas.0711566105CrossRefPubMedPubMedCentral

33.

Musallam KM, Sankaran VG, Cappellini MD, Duca L, Nathan DG, Taher AT (2012) Fetal hemoglobin levels and morbidity in untransfused patients with beta-thalassemia intermedia. Blood 119(2):364–367. https://doi.org/10.1182/blood-2011-09-382408CrossRefPubMed

34.

Meiler SE, Wade M, Kutlar F, Yerigenahally SD, Xue Y, Moutouh-de Parseval LA, Corral LG, Swerdlow PS, Kutlar A (2011) Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. Blood 118(4):1109–1112. https://doi.org/10.1182/blood-2010-11-319137CrossRefPubMedPubMedCentral

35.

DeSimone J, Koshy M, Dorn L, Lavelle D, Bressler L, Molokie R, Talischy N (2002) Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 99(11):3905–3908. https://doi.org/10.1182/blood.v99.11.3905CrossRefPubMed

36.

Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J (2003) Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 102(12):3865–3870. https://doi.org/10.1182/blood-2003-05-1738CrossRefPubMed

37.

Noguchi CT, Rodgers GP, Serjeant G, Schechter AN (1988) Levels of fetal hemoglobin necessary for treatment of sickle cell disease. N Engl J Med 318(2):96–99. https://doi.org/10.1056/NEJM198801143180207CrossRefPubMed

38.

Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, Milner PF, Orringer EP, Phillips G Jr, Platt OS et al (1992) Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 79(10):2555–2565CrossRef

39.

Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, Sinopoulou K, Balassopoulou A, Loukopoulos D, Terpos E (2010) The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 115(12):2354–2363. https://doi.org/10.1182/blood-2009-05-221333CrossRefPubMed

40.

Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A (2014) Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 123(4):481–485. https://doi.org/10.1182/blood-2013-09-528067CrossRefPubMed

41.

Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV, Arrowsmith CH, Brown PJ, Vedadi M, Jin J (2013) Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem 56(21):8931–8942. https://doi.org/10.1021/jm401480rCrossRefPubMed

Titel: UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells
verfasst von: Tiwaporn Nualkaew
Pinyaphat Khamphikham
Phitchapa Pongpaksupasin
Woratree Kaewsakulthong
Duantida Songdej
Kittiphong Paiboonsukwong
Orapan Sripichai
James Douglas Engel
Suradej Hongeng
Suthat Fucharoen
Natee Jearawiriyapaisarn
Publikationsdatum: 21.06.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Annals of Hematology / Ausgabe 9/2020
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-020-04136-w

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 9/2020

Multidrug-related protein 1 (MRP1) polymorphisms rs129081, rs212090, and rs212091 predict survival in normal karyotype acute myeloid leukemia

Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia

Favorable outcomes of acute leukemias of ambiguous lineage treated with hyperCVAD: a multi-center retrospective study

Long non-coding RNA CCAT2 as a potential serum biomarker for diagnosis and prognosis of multiple myeloma

A study of the geographic distribution and associated risk factors of leg ulcers within an international cohort of sickle cell disease patients: the CASiRe group analysis

Coagulopathy and thromboembolic events in patients with SARS-CoV-2 infection: pathogenesis and management strategies

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin