IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia

Xiaolin Hu, Dafeng Yang, Mary Zimmerman, Feiyan Liu, Jine Yang, Swati Kannan, Andreas Burchert, Zdzislaw Szulc, Alicja Bielawska, Keiko Ozato, Kapil Bhalla, Kebin Liu

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit uncontrolled clonal expansion of undifferentiated myeloid cells that can progress to a fatal blast crisis, thereby resembling human chronic myelogeneous leukemia (CML). Therefore, IRF8 is a myeloid leukemia suppressor. Whereas the understanding of IRF8 function in CML has recently improved, the molecular mechanisms underlying IRF8 function in CML are still largely unknown. In this study, we identified acid ceramidase (ACDase) as a general transcription target of IRF8. We demonstrated that IRF8 expression is regulated by IRF8 promoter DNA methylation in myeloid leukemia cells. Restoration of IRF8 expression repressed A-CDase expression, resulting in C16 ceramide accumulation and increased sensitivity of CML cells to FasL-induced apoptosis. In myeloid cells derived from IRF8-deficient mice, A-CDase protein level was dramatically increased. Furthermore, we demonstrated that IRF8 directly binds to the A-CDase promoter. At the functional level, inhibition of A-CDase activity, silencing A-CDase expression, or application of exogenous C16 ceramide sensitized CML cells to FasL-induced apoptosis, whereas overexpression of A-CDase decreased CML cells' sensitivity to FasL-induced apoptosis. Consequently, restoration of IRF8 expression suppressed CML development in vivo at least partially through a Fas-dependent mechanism. In summary, our findings determine the mechanism of IRF8 downregulation in CML cells and they determine a primary pathway of resistance to Fasmediated apoptosis and disease progression.

Original languageEnglish (US)
Pages (from-to)2882-2891
Number of pages10
JournalCancer Research
Volume71
Issue number8
DOIs
StatePublished - Apr 15 2011

Fingerprint

Acid Ceramidase
Leukemia
Apoptosis
Myeloid Cells
Myeloid Leukemia
Blast Crisis
DNA Methylation
Disease Progression
Cell Differentiation
Transcription Factors
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia. / Hu, Xiaolin; Yang, Dafeng; Zimmerman, Mary; Liu, Feiyan; Yang, Jine; Kannan, Swati; Burchert, Andreas; Szulc, Zdzislaw; Bielawska, Alicja; Ozato, Keiko; Bhalla, Kapil; Liu, Kebin.

In: Cancer Research, Vol. 71, No. 8, 15.04.2011, p. 2882-2891.

Research output: Contribution to journalArticle

Hu, X, Yang, D, Zimmerman, M, Liu, F, Yang, J, Kannan, S, Burchert, A, Szulc, Z, Bielawska, A, Ozato, K, Bhalla, K & Liu, K 2011, 'IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia', Cancer Research, vol. 71, no. 8, pp. 2882-2891. https://doi.org/10.1158/0008-5472.CAN-10-2493
Hu, Xiaolin ; Yang, Dafeng ; Zimmerman, Mary ; Liu, Feiyan ; Yang, Jine ; Kannan, Swati ; Burchert, Andreas ; Szulc, Zdzislaw ; Bielawska, Alicja ; Ozato, Keiko ; Bhalla, Kapil ; Liu, Kebin. / IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia. In: Cancer Research. 2011 ; Vol. 71, No. 8. pp. 2882-2891.
@article{6ecd0f7076f246b6a9154de6537c7518,
title = "IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia",
abstract = "IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit uncontrolled clonal expansion of undifferentiated myeloid cells that can progress to a fatal blast crisis, thereby resembling human chronic myelogeneous leukemia (CML). Therefore, IRF8 is a myeloid leukemia suppressor. Whereas the understanding of IRF8 function in CML has recently improved, the molecular mechanisms underlying IRF8 function in CML are still largely unknown. In this study, we identified acid ceramidase (ACDase) as a general transcription target of IRF8. We demonstrated that IRF8 expression is regulated by IRF8 promoter DNA methylation in myeloid leukemia cells. Restoration of IRF8 expression repressed A-CDase expression, resulting in C16 ceramide accumulation and increased sensitivity of CML cells to FasL-induced apoptosis. In myeloid cells derived from IRF8-deficient mice, A-CDase protein level was dramatically increased. Furthermore, we demonstrated that IRF8 directly binds to the A-CDase promoter. At the functional level, inhibition of A-CDase activity, silencing A-CDase expression, or application of exogenous C16 ceramide sensitized CML cells to FasL-induced apoptosis, whereas overexpression of A-CDase decreased CML cells' sensitivity to FasL-induced apoptosis. Consequently, restoration of IRF8 expression suppressed CML development in vivo at least partially through a Fas-dependent mechanism. In summary, our findings determine the mechanism of IRF8 downregulation in CML cells and they determine a primary pathway of resistance to Fasmediated apoptosis and disease progression.",
author = "Xiaolin Hu and Dafeng Yang and Mary Zimmerman and Feiyan Liu and Jine Yang and Swati Kannan and Andreas Burchert and Zdzislaw Szulc and Alicja Bielawska and Keiko Ozato and Kapil Bhalla and Kebin Liu",
year = "2011",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-10-2493",
language = "English (US)",
volume = "71",
pages = "2882--2891",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia

AU - Hu, Xiaolin

AU - Yang, Dafeng

AU - Zimmerman, Mary

AU - Liu, Feiyan

AU - Yang, Jine

AU - Kannan, Swati

AU - Burchert, Andreas

AU - Szulc, Zdzislaw

AU - Bielawska, Alicja

AU - Ozato, Keiko

AU - Bhalla, Kapil

AU - Liu, Kebin

PY - 2011/4/15

Y1 - 2011/4/15

N2 - IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit uncontrolled clonal expansion of undifferentiated myeloid cells that can progress to a fatal blast crisis, thereby resembling human chronic myelogeneous leukemia (CML). Therefore, IRF8 is a myeloid leukemia suppressor. Whereas the understanding of IRF8 function in CML has recently improved, the molecular mechanisms underlying IRF8 function in CML are still largely unknown. In this study, we identified acid ceramidase (ACDase) as a general transcription target of IRF8. We demonstrated that IRF8 expression is regulated by IRF8 promoter DNA methylation in myeloid leukemia cells. Restoration of IRF8 expression repressed A-CDase expression, resulting in C16 ceramide accumulation and increased sensitivity of CML cells to FasL-induced apoptosis. In myeloid cells derived from IRF8-deficient mice, A-CDase protein level was dramatically increased. Furthermore, we demonstrated that IRF8 directly binds to the A-CDase promoter. At the functional level, inhibition of A-CDase activity, silencing A-CDase expression, or application of exogenous C16 ceramide sensitized CML cells to FasL-induced apoptosis, whereas overexpression of A-CDase decreased CML cells' sensitivity to FasL-induced apoptosis. Consequently, restoration of IRF8 expression suppressed CML development in vivo at least partially through a Fas-dependent mechanism. In summary, our findings determine the mechanism of IRF8 downregulation in CML cells and they determine a primary pathway of resistance to Fasmediated apoptosis and disease progression.

AB - IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit uncontrolled clonal expansion of undifferentiated myeloid cells that can progress to a fatal blast crisis, thereby resembling human chronic myelogeneous leukemia (CML). Therefore, IRF8 is a myeloid leukemia suppressor. Whereas the understanding of IRF8 function in CML has recently improved, the molecular mechanisms underlying IRF8 function in CML are still largely unknown. In this study, we identified acid ceramidase (ACDase) as a general transcription target of IRF8. We demonstrated that IRF8 expression is regulated by IRF8 promoter DNA methylation in myeloid leukemia cells. Restoration of IRF8 expression repressed A-CDase expression, resulting in C16 ceramide accumulation and increased sensitivity of CML cells to FasL-induced apoptosis. In myeloid cells derived from IRF8-deficient mice, A-CDase protein level was dramatically increased. Furthermore, we demonstrated that IRF8 directly binds to the A-CDase promoter. At the functional level, inhibition of A-CDase activity, silencing A-CDase expression, or application of exogenous C16 ceramide sensitized CML cells to FasL-induced apoptosis, whereas overexpression of A-CDase decreased CML cells' sensitivity to FasL-induced apoptosis. Consequently, restoration of IRF8 expression suppressed CML development in vivo at least partially through a Fas-dependent mechanism. In summary, our findings determine the mechanism of IRF8 downregulation in CML cells and they determine a primary pathway of resistance to Fasmediated apoptosis and disease progression.

UR - http://www.scopus.com/inward/record.url?scp=79954578082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79954578082&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-2493

DO - 10.1158/0008-5472.CAN-10-2493

M3 - Article

C2 - 21487040

AN - SCOPUS:79954578082

VL - 71

SP - 2882

EP - 2891

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 8

ER -