Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr–abl oncogene

Huang, Weiqi; Bei, Ling; Eklund, Elizabeth A.

doi:10.3109/10428194.2012.720979

Cited by 14 publications

(26 citation statements)

References 33 publications

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“…We have found previously that increased expression of Fap1 and Gas2 in Bcr-abl ϩ myeloid progenitor cells, because of decreased Icsbp, resulted in Fas resistance and ␤-catenin activation (21)(22)(23)35). This study implicates the same pathways in sustained granulocyte production during emergency granulopoiesis in the absence of Icsbp.…”

Section: Discussionsupporting

confidence: 58%

“…We found Fap1-dependent Fas resistance in Bcrabl ϩ and Icsbp Ϫ/Ϫ bone marrow progenitors (21,23). Fap1 also interacts with adenomatous polyposis coli protein, facilitating Gsk3␤ inactivation (dephosphorylation) by Fap1 (35).…”

mentioning

confidence: 79%

“…Interaction of Fap1 with Fas or adenomatous polyposis coli protein is blocked by a tripeptide representing the Fas C terminus (SLV) (21,23,35). We employed this peptide to investigate the functional consequences of increased Fap1 expression in Icsbp Ϫ/Ϫ mice.…”

Section: Figure 4 Icsbp Target Genes Were Differentially Regulated Imentioning

confidence: 99%

“…Ubiquitination and proteasomal degradation of ␤-catenin is enhanced by Gsk3␤-induced phosphorylation, and ␤-catenin is stabilized in Bcr-abl ϩ or Icsbp Ϫ/Ϫ cells via this mechanism (35). In vitro, the effects of Fap1 were inhibited by a Fas-C-terminal tripeptide that blocks a Fap1 protein/protein interaction domain (SLV peptide) (21,23,35).…”

mentioning

confidence: 99%

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The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis

Hu¹,

Huang

Hjort³

et al. 2016

Journal of Biological Chemistry

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Emergency granulopoiesis occurs in response to infectious or inflammatory challenge and is a component of the innate immune response. Some molecular events involved in initiating emergency granulopoiesis are known, but termination of this process is less well defined. In this study, we found that the interferon consensus sequence binding protein (Icsbp/Irf8) was required to terminate emergency granulopoiesis. Icsbp is an interferon regulatory transcription factor with leukemia suppressor activity. Expression of Icsbp is decreased in chronic myeloid leukemia, and Icsbp ؊/؊ mice exhibit progressive granulocytosis with evolution to blast crisis, similar to the course of human chronic myeloid leukemia. In this study, we found aberrantly sustained granulocyte production in Icsbp ؊/؊ mice after stimulation of an emergency granulopoiesis response. Icsbp represses transcription of the genes encoding Fas-associated phosphatase 1 (Fap1) and growth arrest-specific 2 (Gas2) and activates genes encoding Fanconi C and F. After stimulation of emergency granulopoiesis, we found increased and sustained expression of Fap1 and Gas2 in bone marrow myeloid progenitor cells from Icsbp ؊/؊ mice in comparison with the wild type.This was associated with resistance to Fas-induced apoptosis and increased ␤-catenin activity in these cells. We also found that repeated episodes of emergency granulopoiesis accelerated progression to acute myeloid leukemia in Icsbp ؊/؊ mice. This was associated with impaired Fanconi C and F expression and increased sensitivity to DNA damage in bone marrow myeloid progenitors. Our results suggest that impaired Icsbp expression enhances leukemogenesis by deregulating processes that normally limit granulocyte expansion during the innate immune response.

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Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 79%

Section: Figure 4 Icsbp Target Genes Were Differentially Regulated Imentioning

confidence: 99%

mentioning

confidence: 99%

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The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis

Hu¹,

Huang

Hjort³

et al. 2016

Journal of Biological Chemistry

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“…Fas resistance in CML is not due to decreased Fas or Fas ligand, but our studies suggested a role for Fas inhibition by Fas-associated phosphatase 1 (Fap1). 13–16 During progression to blast crisis (BC), β-catenin activity increases, expanding the LSC pool. 14,17 Increased β-catenin activity in CML is not due to altered Wnt or Wnt receptors, but our studies implicated glycogen synthase kinase-3β (Gsk3β) inhibition by Fap1.…”

Section: Introductionmentioning

confidence: 99%

The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

et al. 2016

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Chronic myeloid leukemia (CML) is characterized by expression of Bcr-abl, a tyrosine kinase oncogene. Clinical outcomes in CML were revolutionized by development of Bcr-abl-targeted tyrosine kinase inhibitors (TKIs), but CML is not cured by these agents. CML leukemia stem cells (LSCs) are relatively TKI insensitive and persist even in remission. LSC persistence results in relapse upon TKI discontinuation, or drug resistance or blast crisis (BC) during prolonged treatment. We hypothesize that increased expression of Fas-associated phosphatase 1 (Fap1) in CML contributes to LSC persistence and BC. As Fap1 substrates include Fas and glycogen synthase kinase-3β (Gsk3β), increased Fap1 activity in CML is anticipated to induce Fas resistance and stabilization of β-catenin protein. Resistance to Fas-induced apoptosis may contribute to CML LSC persistence, and β-catenin activity increases during BC. In the current study, we directly tested the role of Fap1 in CML LSC persistence using in an in vivo murine model. In TKI-treated mice, we found that inhibiting Fap1, using a tripeptide or small molecule, prevented TKI resistance, BC and relapse after TKI discontinuation; all events observed with TKI alone. In addition, Fap1 inhibition increased Fas sensitivity and decreased β-catenin activity in CD34+ bone marrow cells from human subjects with CML. Therapeutic Fap1 inhibition may permit TKI discontinuation and delay in progression in CML.

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Non-transmembrane PTPs in Cancer

Hendriks

Böhmer

2016

Protein Tyrosine Phosphatases in Cancer

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Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr–abl oncogene

Cited by 14 publications

References 33 publications

The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis

The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis

The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

Non-transmembrane PTPs in Cancer

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