Loss of Irf8 does not co-operate with overexpression of BCL-2 in the induction of leukemias<i>in vivo</i>

Koenigsmann, Jessica; Carstanjen, Dirk

doi:10.3109/10428190903296913

Cited by 5 publications

(6 citation statements)

References 19 publications

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“…It has been shown that IRF8 represses Bcl-2 expression in myeloid cells in vitro (39). However, it has also been shown that IRF8 does not regulate Bcl-2 expression in myeloid cells in vivo (76). In our study the IRF8 expression level is inversely correlated with Bcl-2 expression level in tumor-induced MDSCs.…”

Section: Discussionmentioning

confidence: 38%

Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

Bardhan

Paschall

et al. 2013

Journal of Biological Chemistry

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Background:The mechanism underlying MDSC persistence in tumor-bearing hosts is elusive. Results: IRF8 is down-regulated in MDSCs, resulting in Fas, Bax, and Bcl-xL deregulation and decreased spontaneous apoptosis. Conclusion: Increased resistance to Fas-mediated apoptosis is at least partially responsible for MDSC accumulation. Significance: Targeting Bcl-xL is potentially an effective approach to suppress MDSCs in cancer therapy.

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Section: Discussionmentioning

confidence: 38%

Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

Bardhan

Paschall

et al. 2013

Journal of Biological Chemistry

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“…The function of IRF8 in apoptosis and tumor suppression has also been demonstrated in other non-hematopoietic cells (27, 32, 37, 49). However, it has been shown that the correlation between IRF8 and the Bcl-2 family members observed in vitro is not observed in vivo (21). Our data suggest that IRF8 is a transcription repressor of A-CDase in myeloid leukemia cells in vitro and in primary myeloid cells in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…Based on these observations, we propose that the Fas-mediated effector mechanism of the host T lymphocytes plays an important role in the elimination of unwanted cells during myeloid cell linage differentiation to maintain normal homeostasis. IRF8 regulates A-CDase and potentially other apoptosis-related genes (15, 18–21) to maintain myeloid cell sensitivity to Fas-mediated apoptosis for normal homeostasis. Loss of IRF8 expression (i.e.…”

Section: Discussionmentioning

confidence: 99%

IRF8 Regulates Acid Ceramidase Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia

Yang

Zimmerman

et al. 2011

Cancer Research

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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. Cancer Res; 71(8); 2882-91. Ó2011 AACR.

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“…The function of IRF8 in apoptosis has also been demonstrated in other non-hematopoietic cells (17, 22-24). In addition, it has been shown that the correlation between IRF8 and the Bcl-2 family members observed in vitro may not be observed in vivo (10). Therefore, IRF8’s function in regulation of apoptosis-related genes might be cell type-dependent and different between in vitro and in vivo conditions.…”

Section: Discussionmentioning

confidence: 99%

“…However, these studies also suggest that regulation of apoptosis-related genes by IRF8 is cell type-dependent. Furthermore, it has been shown that regulation of Bcl-2 by IRF8 observed in vitro might not be observed in vivo (10). …”

Section: Introductionmentioning

confidence: 99%

Cutting Edge: IRF8 Regulates Bax Transcription In Vivo in Primary Myeloid Cells

Yang

Zimmerman

et al. 2011

The Journal of Immunology

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A prominent phenotype of IRF8 knock out (IRF8 KO) mice is the uncontrolled expansion of immature myeloid cells. The molecular mechanism underlying this myeloproliferative syndrome is still elusive. In this study, we observed that Bax expression level is low in bone marrow (BM) preginitor cells and increased dramatically in primary myeloid cells in wt mice. In contrast, Bax expression level remained at low level in primary myeloid cells in IRF8 KO mice. However, in vitro IRF8 KO BM-differentiated myeloid cells expressed Bax at a level as high as that in wt myeloid cells. Furthermore, we demonstrated that IRF8 specifically binds to the Bax promoter region in primary myeloid cells. Functional analysis indicated that IRF8 deficiency results in increased resistance of the primary myeloid cells to Fas-mediated apoptosis. Our findings thus determine that IRF8 directly regulates Bax transcription in vivo but no in vitro during myeloid cell lineage differentiation.

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Loss of Irf8 does not co-operate with overexpression of BCL-2 in the induction of leukemiasin vivo

Cited by 5 publications

References 19 publications

Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

IRF8 Regulates Acid Ceramidase Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia

Cutting Edge: IRF8 Regulates Bax Transcription In Vivo in Primary Myeloid Cells

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