C/EBPβ is a Critical Mediator of IFN-α-induced Exhaustion of Chronic Myeloid Leukemia Stem Cells

Overview

Journal Blood Adv

Specialty Hematology

Date 2019 Feb 14

PMID 30755436

Citations 13

Authors

Asumi Yokota

Hideyo Hirai

Ryuichi Sato

Hiroko Adachi

Fumiko Sato

Yoshihiro Hayashi

Atsushi Sato

Naoka Kamio

Yasuo Miura

Masakazu Nakano

Daniel G Tenen

Shinya Kimura

Kei Tashiro

Taira Maekawa

Affiliations

Soon will be listed here.

Abstract

Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-α (IFN-α) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-α upregulated CCAAT/enhancer binding protein β (C/EBPβ) in BCR-ABL-expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 3' distal enhancer of that contains tandemly aligned IFN-γ-activated site elements. Suppression or deletion of the IFN-γ-activated site elements abrogated IFN-α-dependent upregulation of C/EBPβ. IFN-α induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPβ-dependent manner. In addition, IFN-α upregulated C/EBPβ and induced exhaustion of lineage CD34 cells from CML patients. Collectively, these results clearly indicate that C/EBPβ is a critical mediator of IFN-α-induced differentiation and exhaustion of CML stem cells.

Citing Articles

scCASE: accurate and interpretable enhancement for single-cell chromatin accessibility sequencing data.

Tang S, Cui X, Wang R, Li S, Li S, Huang X Nat Commun. 2024; 15(1):1629.

PMID: 38388573 PMC: 10884038. DOI: 10.1038/s41467-024-46045-w.

Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia.

Xie X, Zhang W, Zhou X, Xu B, Wang H, Qiu Y Oncogene. 2023; 42(50):3657-3669.

PMID: 37872214 DOI: 10.1038/s41388-023-02874-5.

BCR-ABL1-driven exosome-miR130b-3p-mediated gap-junction Cx43 MSC intercellular communications imply therapies of leukemic subclonal evolution.

Chai C, Sui K, Tang J, Yu H, Yang C, Zhang H Theranostics. 2023; 13(12):3943-3963.

PMID: 37554265 PMC: 10405834. DOI: 10.7150/thno.83178.

Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.

Wu J, Li J, Chen K, Liu G, Zhou Y, Chen W Proc Natl Acad Sci U S A. 2022; 120(1):e2209062120.

PMID: 36577070 PMC: 9910619. DOI: 10.1073/pnas.2209062120.

Loss of G0/G1 switch gene 2 (G0S2) promotes disease progression and drug resistance in chronic myeloid leukaemia (CML) by disrupting glycerophospholipid metabolism.

Gonzalez M, Olivas I, Bencomo-Alvarez A, Rubio A, Barreto-Vargas C, Lopez J Clin Transl Med. 2022; 12(12):e1146.

PMID: 36536477 PMC: 9763536. DOI: 10.1002/ctm2.1146.

References

Madapura H, Nagy N, Ujvari D, Kallas T, Krohnke M, Amu S . Interferon γ is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells. Oncogene. 2017; 36(32):4619-4628. DOI: 10.1038/onc.2017.85. View

Sawai C, Babovic S, Upadhaya S, Knapp D, Lavin Y, Lau C . Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals. Immunity. 2016; 45(3):597-609. PMC: 5054720. DOI: 10.1016/j.immuni.2016.08.007. View

Rowley J . Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973; 243(5405):290-3. DOI: 10.1038/243290a0. View

Essers M, Offner S, Blanco-Bose W, Waibler Z, Kalinke U, Duchosal M . IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009; 458(7240):904-8. DOI: 10.1038/nature07815. View

Zhao C, Chen A, Jamieson C, Fereshteh M, Abrahamsson A, Blum J . Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009; 458(7239):776-9. PMC: 2946231. DOI: 10.1038/nature07737. View

Zhao C, Blum J, Chen A, Kwon H, Jung S, Cook J . Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007; 12(6):528-41. PMC: 2262869. DOI: 10.1016/j.ccr.2007.11.003. View

Skokowa J, Klimiankou M, Klimenkova O, Lan D, Gupta K, Hussein K . Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nat Med. 2012; 18(10):1550-9. PMC: 3941918. DOI: 10.1038/nm.2958. View

Burchert A, Wolfl S, Schmidt M, Brendel C, Denecke B, Cai D . Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood. 2002; 101(1):259-64. DOI: 10.1182/blood-2002-02-0659. View

Druker B, Talpaz M, Resta D, Peng B, Buchdunger E, Ford J . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344(14):1031-7. DOI: 10.1056/NEJM200104053441401. View

10.

Burchert A, Muller M, Kostrewa P, Erben P, Bostel T, Liebler S . Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol. 2010; 28(8):1429-35. DOI: 10.1200/JCO.2009.25.5075. View

11.

Hochhaus A, Reiter A, Saussele S, Reichert A, Emig M, Kaeda J . Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML.... Blood. 1999; 95(1):62-6. View

12.

Walter M, Look D, Tidwell R, Roswit W, Holtzman M . Targeted inhibition of interferon-gamma-dependent intercellular adhesion molecule-1 (ICAM-1) expression using dominant-negative Stat1. J Biol Chem. 1997; 272(45):28582-9. DOI: 10.1074/jbc.272.45.28582. View

13.

Mullally A, Bruedigam C, Poveromo L, Heidel F, Purdon A, Vu T . Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera. Blood. 2013; 121(18):3692-702. PMC: 3643767. DOI: 10.1182/blood-2012-05-432989. View

14.

Matte-Martone C, Liu J, Zhou M, Chikina M, Green D, Harty J . Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity. J Clin Invest. 2017; 127(7):2765-2776. PMC: 5490746. DOI: 10.1172/JCI85736. View

15.

Satake S, Hirai H, Hayashi Y, Shime N, Tamura A, Yao H . C/EBPβ is involved in the amplification of early granulocyte precursors during candidemia-induced "emergency" granulopoiesis. J Immunol. 2012; 189(9):4546-55. DOI: 10.4049/jimmunol.1103007. View

16.

Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y . TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010; 463(7281):676-80. DOI: 10.1038/nature08734. View

17.

Moriggl R, Gouilleux-Gruart V, Jahne R, Berchtold S, Gartmann C, Liu X . Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol Cell Biol. 1996; 16(10):5691-700. PMC: 231569. DOI: 10.1128/MCB.16.10.5691. View

18.

Tecchio C, Huber V, Scapini P, Calzetti F, Margotto D, Todeschini G . IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells. Blood. 2004; 103(10):3837-44. DOI: 10.1182/blood-2003-08-2806. View

19.

Masarova L, Patel K, Newberry K, Cortes J, Borthakur G, Konopleva M . Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017; 4(4):e165-e175. PMC: 5421384. DOI: 10.1016/S2352-3026(17)30030-3. View

20.

Sato T, Onai N, Yoshihara H, Arai F, Suda T, Ohteki T . Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med. 2009; 15(6):696-700. DOI: 10.1038/nm.1973. View